2-aminopyridines containing fused ring substituents

ABSTRACT

The present invention relates to 2-aminopyridine derivatives of the formula  
                 
 
     wherein G, R 1  and R 2  are defined as in the specification, that exhibit activity as nitric oxide synthase (NOS) inhibitors, to pharmaceutical compositions containing them and to their use in the treatment and prevention of central nervous system and other disorders.

[0001] The present invention relates to certain 2-aminopyridinescontaining fused ring substituents that exhibit activity as nitric oxidesynthase (NOS) inhibitors, to pharmaceutical compositions containingthem and to their use in the treatment and prevention of central nervoussystem disorders, inflammatory disorders, septic shock and otherdisorders.

[0002] There are three known isoforms of NOS—an inducible form (I-NOS)and two constitutive forms referred to as, respectively, neuronal NOS(N-NOS) and endothelial NOS (E-NOS). Each of these enzymes carries outthe conversion of arginine to citrulline while producing a molecule ofnitric oxide (NO) in response to various stimuli. It is believed thatexcess nitric oxide (NO) production by NOS plays a role in the pathologyof a number of disorders and conditions in mammals. For example, NOproduced by I-NOS is thought to play a role in diseases that involvesystemic hypotension such as toxic shock and therapy with certaincytokines. It has been shown that cancer patients treated with cytokinessuch as interleukin 1 (IL-1), interleukin 2 (IL-2) or tumor necrosisfactor (TNF) suffer cytokine-induced shock and hypotension due to NOproduced from macrophages, i.e., inducible NOS (I-NOS), see Chemical &Engineering News, December 20, p. 33, (1993). I-NOS inhibitors canreverse this. It is also believed that I-NOS plays a role in thepathology of diseases of the central nervous system such as ischemia.For example, inhibition of I-NOS has been shown to ameliorate cerebralischemic damage in rats, see Am. J. Physiol., 268, p. R286 (1995)).Suppression of adjuvant induced arthritis by selective inhibition ofI-NOS is reported in Eur. J. Pharmacol., 273, p. 15-24 (1995).

[0003] NO produced by N-NOS is thought to play a role in diseases suchas cerebral ischemia, pain, and opiate tolerance. For example,inhibition of N-NOS decreases infarct volume after proximal middlecerebral artery occlusion in the rat, see J. Cerebr. Blood Flow Metab.,14, p. 924-929 (1994). N-NOS inhibition has also been shown to beeffective in antinociception, as evidenced by activity in the late phaseof the formalin-induced hindpaw licking and acetic acid-inducedabdominal constriction assays, see Br. J. Pharmacol., 110, p. 219-224(1993). In addition, subcutaneous injection of Freund's adjuvant in therat induces an increase in NOS-positive neurons in the spinal cord thatis manifested in increased sensitivity to pain, which can be treatedwith NOS inhibitors, see Japanese Journal of Pharmacology, 75, p.327-335 (1997). Finally, opioid withdrawal in rodents has been reportedto be reduced by N-NOS inhibition, see Neuropsychopharmacol., 13, p.269-293 (1995).

SUMMARY OF THE INVENTION

[0004] This invention relates to compounds of the formula

[0005] wherein ring A is a fused 5-7 membered saturated or unsaturatedring wherein from zero to two of the ring members are heteroatomsselected, independently, from nitrogen, oxygen and sulfur, with theproviso that no two adjecent ring members can both be heteroatoms;

[0006] X is oxygen or a bond;

[0007] n is an interger from two to six; and

[0008] R¹ and R² are selected, independently, from (C₁-C₆) alkyl, aryl,tetrahydronaphthalene and aralkyl, wherein said aryl and the aryl moietyof said aralkyl is phenyl or naphthyl and the alkyl moiety is straightor branched and contains from 1 to 6 carbon atoms, and wherein said(C₁-C₆) alkyl, said aryl, said tetrahydronaphthalene and the aryl moietyof said aralkyl may optionally be substituted with from one to threesubstituents, preferably from zero to two substituents, that areselected, independently, from halo (e.g., chloro, fluoro, bromo, iodo),nitro, hydroxy, cyano, amino, (C₁-C₄) alkoxy, and (C₁-C₄) alkylamino;

[0009] or R¹ and R² form, together with the nitrogen to which they areattached, a piperazine, azetidine, piperidine or pyrrolidine ring or anazabicyclic ring containing from 6 to 14 ring members, from 1 to 3 ofwhich are nitrogen and the rest of which are carbon, wherein examples ofsaid azabicyclic rings are the following

[0010] also R¹ or R² may be connected onto the (CH2)_(n) group to form aring of from 4 to 7 members;

[0011] wherein R³ and R⁴ are selected from hydrogen, (C₁-C₆)alkyl,phenyl, naphthyl, (C₁-C₆) alkyl-C(═O)—, HC(═O)—, (C₁-C₆)alkoxy-(C═O)—,phenyl-C(═O)—, naphthyl-C(═O)—, and R⁶R⁷NC(═O)— wherein R⁶ and R⁷ areselected, independently, from hydrogen and (C₁-C₆)alkyl;

[0012] R⁵ is selected from hydrogen, (C₁-C₆)alkyl, phenyl, naphthyl,phenyl-(C₁-C₆)alkyl- and naphthyl(C₁-C₆)alkyl-;

[0013] and wherein said piperazine, azetidine, piperidine andpyrrolidine rings may optionally be substituted with one or moresubstituents, preferably with from zero to two substituents that areselected, independently, from (C₁-C₆)alkyl, amino, (C₁-C₆) alkylamino,[di-(C₁-C₆)alkyl]amino, phenyl substituted 5 to 6 membered heterocyclicrings containing from 1 to 4 rings nitrogen atoms, benzoyl,benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl andphenoxycarbonyl, and wherein the phenyl moieties of any of the foregoingsubstituents may optionally be substituted with one or moresubstituents, preferably with from zero to two substituents, that areselected, independently, from halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, nitro,amino, cyano, CF₃ and OCF₃;

[0014] and the pharmaceutically acceptable salts of such compounds.

[0015] The following compounds are preferred compounds of the invention:

[0016] 6-[4-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0017]6-[4-(2-Pyrrolidin-1-yl-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0018]6-{4-2-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-ethoxy}-naphthalen-1-yl)-pyridin-2-ylamine;

[0019]6-{4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-naphthalen-1-yl)-pyridin-2-ylamine;

[0020]3-{2-[4-(6-Amino-pyridin-2-yl)naphthalen-1-yloxy[-ethyl}3-aza-bicyclo[3.1.0]hex-6-ylamine;

[0021]6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine;

[0022]6-{4-[2-(3-Amino-pyrrolidin-1-yl)-ethoxy]-naphthalen-1-yl}pyridin-2-ylamine;

[0023]6-[4-(1-Benzyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0024]6-[4-(1-Benzyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0025] 6-[4-(Piperidin-4-yloxy)naphthalen-1-yl]-pyridin-2-ylamine;

[0026] 6-[4-(Pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0027]6-[4-(1-Isobutyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0028]6-[4-(1-Furan-2-ylmethyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0029]6-[4-(1-Isobutyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0030]6-[4-(1-Furan-2-ylmethyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0031]6-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0032]6-[4-(2-Diisopropylamino-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0033]6-[4-(1-Methyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0034]6-[4-(1-Methyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0035]6-[4-(3-Dimethylamino-propoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0036]6-[4-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)naphthalen-1-yl]-pyridin-2-ylamine;

[0037]6-{4-(2-Piperidin-1-yl-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0038]6-{4-[2-3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine;

[0039]6-4-[2-(4-Dimethylamino-piperidin-1-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine;

[0040]6-{4-(2-(tert-Butyl-methyl-amino)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine;

[0041]6-{4-[24-Methyl-piperazin-1-yl)-ethoxy]naphthalen-1-yl}-pyridin-2-ylamine;

[0042]6-4-[2-(4-Phenyl-piperidin-1-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine;

[0043]6-{4-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine;

[0044] 6-[4-(Piperidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0045] 6-[4-(1-Methyl-piperidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0046]6-[4-(1-Methyl-piperidin-3-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0047] 6-[4-(2-Amino-cyclohexyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0048] 6-[4-(Piperidin-3-ylmethoxy)-naphthalen-1-yl ]-pyridin-2-ylamine;

[0049]6-[4-(1-Isobutyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0050]6-[4-(1-Furan-2-ylmethyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0051]6-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0052] 6-[4-(Azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0053]6-[4-(1-Methyl-pyrrolidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0054] 6-[4-Azetidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0055] 6-[7-(2-Dimethylamino-ethoxy)-indan-4-yl]-pyridin-2-ylamine;

[0056] 6-[7-(2-Pyrrolidin-1-yl-ethoxy)-indan-4-yl]-pyridin-2-ylamine;

[0057]6-{7-[2-(Benzyl-methyl-amino)-ethoxy]-indan-4-yl}-pyridin-2-ylamine;

[0058]6-{7-[2-(4-Phenethyl-piperazin-1-yl)-ethoxy]-indan-4-yl}-pyridin-2-ylamine;

[0059]6-{7-[2-Isobutyl-piperazin-1-yl)-ethoxy]-indan-4-yl}-pyridin-2-ylamine;

[0060] 6-[7-(2-Morpholin-4-yl-ethoxy)-indan-4-yl]-pyridin-2-ylamine;

[0061] 6-[7-(2-Diisopropylamino-ethoxy)-indan-4-yl]-pyridin-2-ylamine;

[0062]6-{7-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl)-ethoxy]-indan-4-yl}-pyridin-2-ylamine;

[0063]6-{7-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-indan-4-yl}-pyridin-2-ylamine;

[0064] 6-{7-[2-(tert-Butyl-methyl-amino)-ethoxy]-indan-4-yl}-pyridin-2-ylamine;

[0065]6-{7-[2-(4-Dimethylamino-piperidin-1-yl)-ethoxy]-indan-4-yl)-pyridin-2-ylamine;

[0066]6-[8-(2-Dimethylamino-ethoxy)-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl]-pyridin-2-ylamine;

[0067]6-[8-(2-Pyrrolidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl]-pyridin-2-ylamine;

[0068]6-[4-(2-Dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0069]6-[4-(2-Pyrrolidin-1-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0070]6-{4-[2-(tert-Butyl-methyl-amino)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine;

[0071]6-[4-(2-Diisopropylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0072]6-[4-(2-Dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0073]6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl)-pyridin-2-ylamine;

[0074]6-[4-(2-Piperidin-1-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0075]6-[4-(2-Morpholin-4-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0076]6-{4-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl)-ethoxy]-5,6,7,8-tetrahydro-napthalen-1-yl}-pyridin-2-ylamine;

[0077]6-{4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine;

[0078]6-{4-[2-(4-Dimethylamino-piperidin-1-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine;

[0079]6-{4-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl)-ethoxy]-5,6,7,8-tetrahydro-napthalen-1-yl}-pyridin-2-ylamine;

[0080]6-[4(1-Isobutyl-piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0081]6-[4(1-Methyl-piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0082]6-{4-[2-(2-Diethylamino-ethoxy)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine;

[0083]6-[4Piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-napthalen-1-yl]-pyridin-2-ylamine;

[0084]6-[4-(2-Amino-cyclohexyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0085]6-[4-(Pyrrolidin-2-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;and

[0086]6-[4-(2-Dimethylamino-ethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine;

[0087] and the pharmaceutically acceptable salts of the foregoingcompounds.

[0088] The following are additional examples of compounds of thisinvention:

[0089]6-[4-(2-Amino-cyclopentyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0090]6-[4-(2-Amino-cyclobutyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0091]6-[4-(2-Amino-cyclopropyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0092]6-[4-(3-Amino-cyclohexyloxy)-5,6,7,8-tetrahydro-naphthalen1-yl]-pyridin-2-ylamine;

[0093]6-[4-(3-Amino-cyclopentyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0094]6-[4-(3-Amino-cyclobutyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0095]6-[4-(4-Amino-cyclohexyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine;

[0096] 6-[4-(2-Amino-cyclopentyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0097] 6-[4-(2-Amino-cyclobutyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0098] 6-[4-(2-Amino-cyclopropyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0099] 6-[4-(3-Amino-cyclohexyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0100] 6-[4-(3-Amino-cyclopentyloxy)-naphthalen-1-yl-pyridin-2-ylamine;

[0101] 6-[4-(3-Amino-cyclobutyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0102] 6-[4-(4-Amino-cyclohexyloxy)-naphthalen-1-yl]-pyridin-2-ylamine;

[0103] 6-[4-(2-Amino-cyclopentyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0104] 6-[4-(2-Amino-cyclobutyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0105] 6-[4-(2-Amino-cyclopropyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0106] 6-[4-(3-Amino-cyclohexyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0107] 6-[4-(3-Amino-cyclopentyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0108] 6-[(3-Amino-cyclobutyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0109] 6-[4-(4-Amino-cyclohexyloxy)-indan-4-yl]-pyridin-2-ylamine;

[0110]6-[4-Piperidin-3-ylmethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine;

[0111]6-[4-(2-Pyrrolidinyl-ethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine;

[0112]6-[4-(2-Amino-cyclohexyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine;

[0113]6-[4-(2-4-Dimethylamino-piperidin-1-yl)-ethoxy))-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine; and

[0114]6-[4-(2-(4-Methyl-piperazin-1-yl)-ethoxy))-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine.

[0115] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0116] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0117] The term “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

[0118] The terms “halo” and “halogen”, as used herein, unless otherwiseindicated, include chloro, fluoro, bromo and iodo.

[0119] Examples of more specific embodiments of the present inventioninclude:

[0120] (a) compounds of the formula I wherein ring A is pyrrolo;

[0121] (b) compounds of the formula I wherein ring A is pyrido;

[0122] (c) compounds of the formula I wherein X is a bond;

[0123] (d) compounds of the formula I wherein ring A is pyrimido;

[0124] (e) compounds of the formula I wherein n is 2 or 3;

[0125] (f) compounds of the formula I wherein X is oxygen;

[0126] (g) compounds of the formula I wherein R¹ and R² are selected,independently, from (C₁-C₆)alkyl;

[0127] (h) compounds of the formula I wherein R¹ and R² do not form aring with the nitrogen to which they are attached;

[0128] (i) compounds of the formula I wherein R¹ and R² form, togetherwith the nitrogen to which they are attached, a piperazine, azetidine,piperidine or pyrrolidine ring;

[0129] (j) compounds of the formula I wherein R¹ is selected from(C₁-C₆)alkyl and R² is selected from aryl, tetrahydronaphthalene andaralkyl; and

[0130] (k) compounds of the formula I wherein ring A is thieno orthiazolo.

[0131] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a condition selected from thegroup consisting of migraine inflammatory diseases (e.g., asthma),stroke, acute and chronic pain, hypovolemic shock, traumatic shock,reperfusion injury, Crohn's disease, ulcerative colitis, septic shockmultiple sclerosis, AIDS associated dementia, neurodegenerativediseases, neuron toxicity, depression (e.g., major depressive disorderand dysthymia, Parkinson's disease, Alzheimer's disease, chemicaldependencies and addiction (e.g., dependencies on drugs, alcohol andnicotine), emesis, epilepsy, anxiety, psychosis, head trauma, adultrespiratory distress syndrome (ARDS), morphine induced tolerance andwithdrawal symptoms, inflammatory bowel disease, osteoarthritis,rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinalcord injury, Huntington's disease, glaucoma, macular degeneration,diabetic neuropathy, diabetic nephropathy and cancer in a mammal,including a human, comprising an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof that is effective intreating or preventing such condition, and a pharmaceutically acceptablecarrier.

[0132] The present invention also relates to a method of treating orpreventing a condition selected from the group consisting of migraineinflammatory diseases (e.g., asthma), stroke, acute and chronic pain,hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease,ulcerative colitis, septic shock, multiple sclerosis, AIDS associateddementia, neurodegenerative diseases, neuron toxicity, depression (majordepressive disorder and dysthymia), Parkinson's disease, Alzheimer'sdisease, chemical dependencies and addictions (e.g., dependencies ondrugs, alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, headtrauma, adult respiratory distress syndrome (ARDS), morphine inducedtolerance and withdrawal symptoms, inflammatory bowel disease,osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy,acute spinal cord injury, Huntington's disease, glaucoma, maculardegeneration, diabetic neuropathy, diabetic nephropathy and cancer in amammal, including a human, comprising administering to said mammal anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, that is effective in treating or preventing suchcondition.

[0133] The present invention also relates to a pharmaceuticalcomposition for inhibiting nitric oxide synthase (NOS) in a mammal,including a human, comprising an NOS inhibiting effective amount of acompound of the formula I, or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.

[0134] The present invention also relates to a method of inhibiting NOSin a mammal, including a human, comprising administering to said mammala NOS inhibiting effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof.

[0135] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a condition selected from thegroup consisting of migraine, inflammatory diseases (e.g., asthma),stroke, acute and chronic pain, hypovolemic shock, traumatic shock,reperfusion injury, Crohn's disease, ulcerative colitis, septic shock,multiple sclerosis, AIDS associated dementia, neurodegenerativediseases, neuron toxicity, depression (e.g., major depressive disorderand dysthymia), Parkinson's disease, Alzheimer's disease, chemicaldependencies and addictions (e g, dependencies on drugs, alcohol andnicotine), emesis, epilepsy, anxiety, psychosis, head trauma, adultrespiratory distress syndrome (ARDS), morphine induced tolerance andwithdrawal symptoms, inflammatory bowel disease, osteoarthritis,rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinalcord injury, Huntington's disease, glaucoma, macular degeneration,diabetic neuropathy, diabetic nephropathy and cancer in a mammal,including a human, comprising a NOS inhibiting effective amount of acompound of the formula I, or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.

[0136] The present invention also relates to a method of treating orpreventing a condition selected from the group consisting of migraine;inflammatory diseases (e.g., asthma), stroke, acute and chronic pain,hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease,ulcerative colitis, septic shock, multiple sclerosis, AIDS associateddementia, neurodegenerative diseases, neuron toxicity, depression (major depressive disorder and dysthymia), Parkinson's disease,Alzheimer's disease, chemical dependencies and addictions (e.g.,dependencies on drugs, alcohol or nicotine), emesis, epilepsy, anxiety,psychosis, head trauma, adult respiratory distress syndrome (ARDS),morphine induced tolerance and withdrawal symptoms, inflammatory boweldisease, osteoarthritis, rheumatoid arthritis, ovulation, dilatedcardiomyopathy, acute spinal cord injury, Huntington's disease,glaucoma, macular degeneration, diabetic neuropathy, diabeticnephropathy and cancer in a mammal, including a human, comprisingadministering to said mammal a NOS inhibiting effective amount of acompound of the formula II, or a pharmaceutically acceptable saltthereof.

[0137] Compounds of formula I may contain chiral centers and thereforemay exist in different enantiomeric and diastereomeric forms. Thisinvention relates to all optical isomers and all stereoisomers ofcompounds of the formula I and mixtures thereof, and to allpharmaceutical compositions and methods of treatment defined above thatcontain or employ them, respectively.

[0138] Formula I above includes compounds identical to those depictedbut for the fact that one or more hydrogen, carbon or other atoms arereplaced by isotopes thereof. Such compounds may be useful as researchand diagnostic tools in metabolism pharmacokinetic studies and inbinding assays.

DETAILED DESCRIPTION OF THE INVENTION

[0139] The compounds of the formula I may be prepared as described inthe following reaction schemes and discussion. Unless otherwiseindicated, ring A, X, n, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ and structuralformula I in the reaction schemes and discussion that follow are definedas above.

[0140] Scheme 1 illustrates a method of preparing compounds of theformula I wherein X is a bond and ring A is benzo. Schemes 2 and 3illustrate methods of preparing compounds of the formula I wherein X isoxygen and ring A is benzo. The starting materials used in theprocedures of Schemes 1 and 2 are either commercially available, knownin the art or readily obtainable from known compounds by methods thatwill be apparent to those skilled in the art.

[0141] Referring to Scheme 1, the compound of formula II is cooled toabout −70° C. in dry tetrahydrofuran (THF), and then a solution ofn-butyl lithium is added to it The resulting solution is then treatedwith triethyl borate and allowed to warm to room temperature to form thecompound of formula III.

[0142] The compound of formula III is reacted with the compound offormula IV to form the compound of formula V. This reaction is generallycarried out in an aqueous ethanol solvent, in the presence of sodiumcarbonate and tetrakistriphenylphoshine palladium, at about the refluxtemperature.

[0143] The compound of the formula VI can be formed in the followingmanner. First, the compound of formula V is reacted withN-bromosuccinimide (NBS) and bis-(1-cyano1-aza)-cyclohexane in carbontetrachloride and refluxed for about 8 hours, with additional portionsof the initiator being added at about 1, 2 and 4 hours. Afterevaporation of the solvent, the product of this reaction is reacted withtriethylammonium cyanide in methylene chloride at about room temperatureto form the compound of formula VI.

[0144] Saturation of a solution of the compound of formula VI in ethanolwith hydrogen chloride, followed by refluxing the mixture and thenheating in aqueous hydrochloric acid, yields the compound of formulaVII.

[0145] The compound of the formula VII that is formed in the precedingstep can be converted into the compound of formula IA in the followingmanner. First, the compound of formula VII is reacted with theappropriate compound of the formula R²R¹NH andN-ethyl-N-dimethylaminopropyl carbodiimide (EDAC) in the presence of abase. Examples of suitable bases are those selected from trialkylamines,alkali metal carbonates and alkaline earth metal carbonates. Thisreaction is typically conducted in a solvent such as acetonitrile,methylene chloride or N,N-dimethylformamide (DMF), at a temperature fromabout room temperature to about 100° C., preferably at about roomtemperature. Preferably, the reaction is conducted in the presence of acatalytic additive such as N-hydroxysuccinamide or hydroxybenzotriazole.

[0146] The product of the foregoing reaction is then reduced usingmethods well known to those of skill in the art For example, thereduction can be carried out using lithium aluminum hydride intetrahydrofuran, with or without aluminum chloride, or using boranemethyl sulfide in tetrahydrofuran, at a temperature of about −78° C. toabout 0° C., preferably at about −70° C., to yield the desired compoundof formula IA.

[0147] Referring to scheme 2, the compound of formula VIII is reactedwith tetrabutylammonium tribromide in 1,2-dichloroethane at about roomtemperature. The product of this reaction is then treated with benzylbromide and potassium carbonate in a solvent such as acetonitite, atabout the reflux temperature of the reaction mixture, to form thecompound of formula IX.

[0148] The compound of formula IX is then converted into1-benzyloxy-naphthalene-4-boronic acid by the procedure described abovefor preparing the boronic acid derivative of formula III in Scheme 1.

[0149] Reaction of 1-benzyoxy-naphthalene-4-boronic acid with thecompound of formula X in an ethanol solvent, in the presence of sodiumcarbonate and tetrakistriphenyl palladium, at about the refluxtemperature of the reaction mixture, yields the compound of formula XI.

[0150] The compound of formula XI can be converted into the compound offormula XIII using the following two step process. The compound offormula XI is reacted with ammonium formate and ten percent palladium oncarbon, in an ethanol solvent, at about the reflux temperature of thereaction mixture, to yield the analogous compound to that having formulaXI, wherein the benzyloxy group of formula XI is replaced with a hydroxygroup. The compound of formula XII is then formed by reacting the abovehydroxy derivative with 2-bromoethylacetate and potassium carbonate inacetonitrile at about the reflux temperature of the reaction mixture.

[0151] Basic hydrolysis of the compound of formula XII, followed byreaction with N-ethyl-N-3-dimethylaminopropylcarbodiimide (EDAC) and theappropriate compound having the formula R¹R²NH yields the desiredcompound of the formula XIII. The base hydrolysis is typically carriedout using an alkali metal or alkaline earth metal hydroxide in a mixtureof THF, methanol and water at about room temperature. The reaction withR¹R²NH and EDAC is generally carried out using the procedure describedabove for the preparation of compounds of the formula IA from those offormula VII in Scheme 1.

[0152] The compound of formula XIII can be converted into the desiredcompound of formula IB as follows. The compound of formula XIII isreduced to form the corresponding compound wherein the carbonyl group isreplaced by a methylene group, after which the 2,5-dimethylpyrrolylprotecting group is removed. The reduction can be carried out usingmethods well known to those of skill in the art, for example, usinglithium aluminum hydride in tetrahydrofuran, with or without aluminumchloride, or using borane methyl sulfide in tetrahydrofuran, at atemperature of about −78° C. to about 0° C., preferably at about −70° C.

[0153] Removal of the 2,5-dimethylpyrrolyl protecting group can beaccomplished by reaction with hydroxylamine hydrochloride. This reactionis generally carried out in an alcoholic or aqueous alcoholic solvent ata temperature from about room temperature to about the refluxtemperature of the reaction mixture, preferably at about the refluxtemperature, for about 8 to about 72 hours.

[0154] Compounds of the formula I that are identical to those of formulaIB but for the fact that ring A is other than benzo can be prepared inan analogous fashion, starting with the appropriate compound that isanalogous to that of formula VIII, wherein the unsubstituted benzo ringof formula VIII is replaced by a ring other than benzo that is withinthe definition of ring A.

[0155] Referring to Scheme 3, the known 1-fluoronaphthalene (XIV) isbrominated with bromine in acetic acid at a temperature from about roomtemperature to about the reflux temperature of the reaction mixture forabout to about 48 hours, and the bromide cooled to about −70° C. in drytetrahydrofuran (THF), and then a solution of n-butyl lithium is addedto it. The resulting solution is then treated with triethyl borate andallowed to warm to room temperature to form the compound of formula XV.The compound of formula XV is reacted with the compound of formula IV toform the compound of formula XVI. This reaction is generally carried outin an aqueous ethanol solvent, in the presence of sodium carbonate andtetrakistriphenylphoshine palladium, at about the reflux temperature.The compound of formula XVI is then treated with an alkali metalalkoxide prepared from a compound of the formula HO(CH₂)_(n)NR¹R² andsodium hydride in a polar solvent such as dimethylformamide, at atemperature from room temperature to 140° C. for about 1 to about 48hours. This reaction produces the corresponding compound of formulaXVII, which is then deblocked to remove the 2,5-dimethylpyrrolylprotecting group by reaction with hydroxylamine hydrochloride. Thisreaction is generally carried out in an alcoholic or aqueous alcoholicsolvent, at a temperature from about room temperature to about thereflux temperature of the reaction mixture, preferably at about thereflux temperature, for about 8 to about 72 hours.

[0156] Compounds of the formula I that are identical to those of formulaIA and IB but for the fact that ring A is other than benzo can beprepared in an analogous fashion, starting with the appropriate startingmaterials that are analogous to those of formulas VII and XIV, onSchemes 1, 2 and 3 respectively, wherein the unsubstituted benzo ring ofsuch starting materials is replaced by a ring other than benzo that iswithin the definition of ring A.

[0157] The preparation of other compounds of the formula I notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0158] In each of the reactions discussed or illustrated above, pressureis not critical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

[0159] The compounds of formulae I (“the active compounds of thisinvention”) which are basic in nature are capable of forming a widevariety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the active base compounds of, this invention are readily prepared bytreating the base compound with a substantially equivalent amount of thechosen mineral or organic acid in an aqueous solvent medium or in asuitable organic solvent, such as methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is readily obtained.

[0160] The active compounds of this invention and their pharmaceuticallyacceptable salts are useful as NOS inhibitors i.e., they possess theability to inhibit the NOS enzyme in mammals, and therefore they areable to function as therapeutic agents in the treatment of theaforementioned disorders and diseases in an afflicted mammal.

[0161] The active compounds of this invention and their pharmaceuticallyacceptable salts can be administered via either the oral, parenteral ortopical routes. In general, these compounds are most desirablyadministered in dosages ranging from about 0.01 to about 250 mg per day,in single or divided doses (i.e., from 1 to 4 doses per day), althoughvariations will necessarily occur depending upon the species, weight andcondition of the subject being treated and the particular route ofadministration chosen. However, a dosage level that is in the range ofabout 0.07 mg to about 21 mg per kg of body weight per day is mostdesirably employed. Variations may nevertheless occur depending upon thespecies of animal being treated and its individual response to saidmedicament, as well as on the type of pharmaceutical formulation chosenand the time period and interval at which such administration is carriedout. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day.

[0162] The active compounds of the invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the three routes previously indicated, and suchadministration may be carried out in single or multiple doses. Moreparticularly, the novel therapeutic agents of this invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,oral pharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging from about 5.0% to about 70% by weight.

[0163] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0164] For parenteral administration, solutions of an active compound ofthe present invention in either sesame or peanut oil or in aqueouspropylene glycol may be employed. The aqueous solutions should besuitably buffered (preferably pH greater than 8) if necessary and theliquid diluent first rendered isotonic. These aqueous solutions aresuitable for intravenous injection purposes. The oily solutions aresuitable for intraarticular, intramuscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell known to those skilled in the art.

[0165] Additionally, it is also possible to administer the activecompounds of the present invention topically when treating inflammatoryconditions of the skin and this may be done by way of creams, jellies,gels, pastes, patches, ointments and the like, in accordance withstandard pharmaceutical practice.

[0166] The ability of compounds of the formulae I to inhibit NOS may bedetermined using procedures described in the literature. The ability ofcompounds of the formulae I to inhibit endothelial NOS may be determinedby using the procedures described by Schmidt et al. in Proc. Natl. Acad.Sci. U.S.A, 88, pp. 365-369 (1991) and by Pollock et al., in Proc. Natl.Acad. Sci. U.S.A, 88, pp. 10480-10484 (1991). The ability of compoundsof the formulae I to inhibit inducible NOS may be determined using theprocedures described by Schmidt et al., in Proc. Natl. Acad, Sci. U.S.A,88 pp. 365-369 (1991) and by Garvey et al. in J. Biol. Chem., 269, pp.26669-26676 (1994). The ability of the compounds of the formulae I toinhibit neuronal NOS may be determined using the procedure described byBredt and Snyder in Proc. Natl. Acad. Sci. U.S.A, 87, 682-685 (1990).

[0167] Of sixteen compounds of the formula I that were tested, allexhibited an IC₅₀<10 μM for inhibition of either inducible or neuronalNOS.

[0168] The present invention is illustrated by the following examples.It will be understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹H NMR) and ¹³C nuclearmagnetic resonance spectra were measured for solutions indeuterochloroform (CDCl₃) or in CD₃OD or CD₃SOCD₃ and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(TMS). The peak shapes are denoted as follows: s, singlet; d, doublet;t, triplet; q, quartet; m, multiplet, b, broad.

EXAMPLE 1

[0169]6-}4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl}-naphthalen-1-yl)-pyridin-2-ylamineN-t-Butylcarbonyl-6-bromo-pyridyl-2-amine

[0170] To a 125 mL round-bottomed flask equipped with N₂ inlet wereadded 0.865 g (5 mmol) 6-bromo-2-aminopyridine, 0.677 mL (5.5 mmol)trimethylacetyl chloride, 15 mL dry acetonitrile, and 1.045 mL (7.5mmol) triethylamine. The reaction was stirred at room temperature for 14hours, poured into water, and stirred until a solid precipitate hadformed. The solid was filtered, washed with water, and dried to afford1.04 g (81%), mp 87°-90° C.

[0171]¹H-NMR (6, CDCl₃): 1.28 (s, 9H), 7.17 (d, J=8, 1H), 7.52 (t, J=8,1H), 8.00 (bs, 1H), 8.19 (d, J=8, 1H).

[0172]¹³C-NMR (δ, CDCl₃): 27.3, 39.8, 112.2, 123.3, 139.0, 140.5, 151.6,177.1.

[0173] B. 4-Methylnaphthalene-1-boronic Acid

[0174] To a 125 mL round-bottomed flask equipped with N₂ inlet wereadded 1.78 g (11.4 mmol) 1-bromo-4methylnaphthalene and 20 mL drytetrahydrofuran. The solution was cooled to −70° C., and 5.49 mL (13.7mmol) of a 2.5M solution of n-butyl lithium in hexane was added over 5minutes, and the reaction stirred at −70° C. for 10 minutes. Thesolution was then treated with 2.34 mL (13.7 mmol) triethyl borate,stirred 5 minutes at −70° C., then warmed to room temperature andstirred 40 hours. The reaction was quenched with aqueous ammoniumchloride solution, poured into 0.5N hydrochloric acid, and extractedinto ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated to a white solid after trituration withhexane, mp 224°-228° C., 1.9 g (90%).

[0175]¹H-NMR (δ, CDCl₃): 2.63 (s, 3H), 7.25 (m, 1H), 7.3-7.5 (m, 3H),7.75 (m, 1H), 7.95 (m, 1H).

[0176]¹³C-NMR (δ, CDCl₃): 19.4, 124.5, 125.5, 125.7, 126.0, 128.5,128.9, 129.9, 131.6, 134.9, 135.3.

[0177] C.N-t-Butylcarbonyl-6-(4-methylnaphthalen-1-yl)-pyridin-2-ylamine

[0178] To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 975 mg (3.795 mmol)N-t-butylcarbonyl-bromo-pyridyl-2-amine, 706 mg (3.795 mmol)4-methylnaphthalene-1-boronic acid, 1.61 g (15.18 mmol) sodiumcarbonate, 50 mg (0.04 mmol) tetrakistriphenylphosphine palladium, 18 mLethanol, and 2 mL water, and the reaction heated at 80° C. for 13 hours.TLC showed a major spot at R_(f)=0.2 in 15% ethyl acetate in hexane, andLCMS showed a major peak at P+1=319. The reaction was cooled, pouredinto water, and extracted into ethyl acetate. The organic layer waswashed with water and brine, dried over sodium sulfate, and evaporated.The residue was chromatographed on silica gel using hexane/ethyl acetateas eluant to afford 1.25 g (˜100%) of a foam.

[0179]¹H-NMR (δ, CDCl₃): 1.32 (s, 9H), 2.73 (s, 3H), 7.25 (m, 1H),7.3-7.5 (m, 4H), 7.81 (t, J=8, 1 H), 8.00 (d, J=8, 1H), 8.05 (d, J=8,1H), 8.145 (bs, 1H), 8.31 (d, J=8, 1H).

[0180]¹³C-NMR (δ, CDCl₃): 19.7, 27.5, 60.4, 112.1, 121.1, 124.4, 125.8,126.08, 126.11, 126.16, 126.9, 131.1, 132.9, 135.3, 1338.7, 151.3,157.8, 177.3.

[0181] MS (%): 319 (parent+1, 100).

[0182] D.N-t-Butylcarbonyl-6-(4-cyanomethylnaphthalen-1-yl)-pyridin-2-ylamine

[0183] To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 1.21 g (3.795 mmol)N-t-butylcarbonyl-6-(4-methylnaphthalen-1-yl)-pyridin-2-ylamine, 810 mg(4.554 mmol) N-bromosuccinimide, 35 mL carbon tetrachloride, and 10 mgbis-(1-cyano-1-azo)-cyclohexane. The reaction was heated at reflux for atotal of 8 hours as additional portions of initiator were added at 1, 2,and 4 hours. The reaction was cooled, filtered with carbontetrachloride, and evaporated. The red oil, 2.5 g, was used directly.

[0184]¹H-NMR (δ, CDCl₃): 1.33 (s, 9H), 5.00 (s, 2H), 7.26 (d, J=7.5,1H), 7.49 (m, 2H), 7.63 (m, 2H), 7.84 (t, J=8, 1H), 8.02 (d, J=8, 1H),8.115 (bs, 1H), 8.22 (d, J=8, 1H), 8.36 (d, J=7.5, 1H).

[0185]¹³C-NMR (δ, CDCl₃): 27.6, 31.6, 39.9, 112.6, 121.0, 124.1, 126.6,126.7, 127.3, 131.5, 131.7, 134.1, 138.8, 139.5, 151.4, 157.1, 177.35.

[0186] MS (%): 397/399 (parent+1, 100).

[0187] The above oil was taken up in 35 mL dry methylene chloride andtreated with 593 mg (3.795 mmol) tetraethylammonium cyanide, andreaction stirred at room temperature for 13 hours. LCMS showed a majorpeak at P+1=344 and TLC showed a major spot at R_(f)=0.6 in 10% ethylacetate in methylene chloride. The reaction was evaporated, and theresidue chromatographed on silica gel using ethyl acetate in methylenechloride as eluant to afford 1.00 g (77%) of a foam.

[0188]¹H-NMR (δ, CDCl₃): 1.32 (s, 9H), 4.18 (s, 3H), 7.26 (d, J=7.5,1H), 7.53 (m, 2H), 7.63 (m, 2H), 7.84 (t, J=8, 1H), 7.92 (d, J=8, 1H),8.04 (d, J=8.5, 1H), 8.10 (bs, 1H), 8.34 (d, J=8, 1H).

[0189]¹³C-NMR (δ, CDCl₃): 22.0, 27.5, 39.9, 112.6, 121.0, 122.75, 126.0,126.7, 126.9, 127.2, 131.2, 131.4, 138.9, 139.1, 151.4, 156.9, 177.35.

[0190] MS (%): 344 (parent+1, 100).

[0191] E. 6-(4-Carboxymethylnaphthalen-1-yl)-pyridin-2-ylamine

[0192] To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 1.00 g (2.915 mmol)N-t-butylcarbonyl-6-(4-cyanomethylnaphthalen-1-yl)-pyridin-2-ylamine and35 mL ethanol. The solution was saturated with HCl and refluxed 14hours, adding two drops of water once it had reached reflux. Thereaction (LCMS showed P+1=391) was cooled and evaporated, and theresidue taken up in ethyl acetate, washed with aqueous sodiumbicarbonate solution, water, and brine, dried over sodium sulfate, andevaporated to an oil, 1.09 g (96%), which was used directly.

[0193]¹H-NMR (δ, CDCl₃): 1.21 (t, J=7, 3H), 1.31 (s, 9H), 4.09 (s, 2H),4.13 (q, J=7, 2H), 7.25 (d, J=7.5, 1H), 7.4-7.6 (m, 4H), 7.82 (t, J=7.5,1H), 7.99 (d, J=8, 1H), 8.06 (d, J=8, 1H), 8.13 (bs, 1H), 8.31 (d, J=8,1H).

[0194]¹³C-NMR (δ, CDCl₃): 14.2, 27.5, 39.5, 60.4, 61.0, 112.3, 121.1,124.2, 126.3, 126.4, 126.8, 127.5, 131.4, 131.7, 132.5, 137.8, 138.7,151.3, 157.5, 171.4, 177.3.

[0195] MS (%): 391 (parent+1, 100).

[0196] The above oil was taken up in 25 mL 6N hydrochloric acid, andheated at 95°-100° C. for 12 hours. LCMS showed P+1=279. The reactionwas cooled, washed with ether, and evaporated, finally dried undervacuum, to a white solid, 0.85 g (93% overall) of the product as thehydrochloride salt.

[0197] MS (%): 279 (parent+1, 100).

[0198] F.6-(4-(4-(2-Phenylethyl)piperazinylcarbonyl)-methylnaphthalen-1-yl]-pyridin-2-ylamine

[0199] To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 157 mg (0.50 mmol)6-(4-carboxymethylnaphthalen-1-yl)-pyridin-2-ylamine, 95 mg (0.50 mmol)N-phenethylpiperazine, 96 mg (0.50 mmol) N-ethyl,N-3-dimethylaminopropyl-carbodiimide, 0.230 mL (1.65 mmol)triethylamine, 10 mg N-hydroxybenzotriazole, and 7 mL dry acetonitrile.The reaction was stirred at room temperature 12 hours (LCMS showedP+1=451 and TLC showed R_(f)=0.3 in 10% methanol/methylene chloride),then evaporated and the residue chromatographed on silica gel usingmethanol/methylene chloride as eluant to afford the product as a foam,230 mg (˜100%).

[0200]¹H-NMR (δ, CDCl₃): 2.37 (m, 2H), 2.52 (m, 2H), 2.59 (m, 2H), 2.76(m, 2H), 3.46 (m, 2H), 3.76 (m, 2H), 4.17 (s, 2H), 4.73 (bs, 2H, NH₂),6.46 (d, J=8, 1H), 6.83 (d, J=7.5, 1H), 7.1-7.6 (m, 10H), 7.98 (d, J=8,1H), 8.14 (d, J=8.5, 1H).

[0201]¹³C-NMR (8, CDCl₃): 33.4, 38.5, 41.8, 46.1, 52.8, 53.2, 60.2,137.2, 115.2, 123.5, 125.6, 126.1, 126.2, 126.3, 126.5, 127.0, 128.5,128.7, 131.6, 132.2, 138.1, 138.5, 139.9, 157.4, 158.3, 169.7.

[0202] MS (%): 451 (parent+1, 100).

[0203] G.6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0204] To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 200 mg aluminum chloride and 5 mL dry tetrahydrofuran.The solution was cooled to 0° C., and 3.50 mL (3.50 mmol) of a 1.0Msolution of lithium aluminum hydride in tetrahydrofuran was added.Stirring was continued at room temperature for 20 minutes, then thesolution was cooled to −70° C., and a solution of 225 mg (0.50 mmol)6-(4-(4-2-phenylethyl)piperazinylcarbonyl)-methylnaphthalen-1-yl)-pyridin-2-ylaminein 7 mL dry tetrahydrofuran was added. Stirring was continued 1 hour at−70° C., then 2 hours at room temperature (LCMS showed P+1=437),followed by careful quenching with 5 mL 1N hydrochloric acid. Afterstirring for 20 minutes (min.), the reaction was treated with 6 mL 6Naqueous sodium hydroxide solution, and extracted with several portionsof methylene chloride. The organic phase was dried over sodium sulfateand evaporated to afford an oil, which was converted to thehydrochloride salt using HCl in ether, affording the product, 175 mg(64%) as a white solid, mp 80°-105° C.

[0205]¹H-NMR (δ, CDCl₃): 2.65 (m, 6H), 2.76 (m, 4H), 2.84 (m, 4H), 3.33(m, 2H), 4.68 (bs, 2H, NH₂), 6.44 (d, J=8, 1H), 6.85 (d, J=7, 1H),7.1-7.6 (m, 10H), 8.11 (m, 2H).

[0206]¹³C-NMR (δ, CDCl₃): 30.9, 33.7, 53.3, 59.7, 60.6, 106.9, 115.2,123.9, 125.77, 125.83, 126.1, 126.7, 126.9, 128.4, 128.7, 131.4, 132.3,136.9, 137.8, 138.0, 140.4, 157.9, 158.2.

[0207] MS (%): 437 (parent+1, 100).

[0208] Anal. Calc'd. for C₂₉H₃₂N₄.Cl.3/2H₂O.1/2(C₄H₁₀O): C 69.32, H7.69, N 10.43. Found: C 69.46, H 7.35, N 10.36.

EXAMPLE 2

[0209]3-{2-[4-(6-Amino-pyridin-2-yl)naphthalen-1-yl]-ethyl}3-aza-bicyclo[3.1.0]hex-6-ylamine

[0210] Prepared as in Example 1, with an extra deblocking step usingtrifluoroacetic acid in methylene chloride to remove a t-butoxycarbonylprotecting group, in 71% yield, mp 250°-260° C., as the hydrochloridesalt.

[0211]¹H-NMR (δ, CDCl₃): 1.24 (bs, 2H), 1.36 (bs, 1H), 2.43 (m, 2H),2.72 (m, 2H), 3.1-3.2 (m, 4H), 4.63 (bs, 2H, NH₂), 6.45 (d, J=8, 1 H),6.83 (d, J=7, 1 H), 7.3-7.6 (m, 5H), 8.07 (m, 2H).

[0212]¹³C-NMR (δ, CDCl₃): 25.8, 29.7, 32.7, 55.0, 56.7, 106.8, 115.2,123.9, 125.7, 125.9, 126.6, 126.8, 131.5, 132.2, 137.1, 137.6, 138.0,157.9, 158.1.

[0213] MS (%): 345 (parent+1, 100).

[0214] Anal. Calc'd. for C₂₂H₂₄N₄.7/4HCl.(C₄H₁₀O): C 64.74, H 7.47, N11.61. Found: C 64.34, H 6.94, N 11.20.

EXAMPLE 3

[0215]6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0216] Prepared as in Example 1, in 74% yield, mp 225°-235° C., as thehydrochloride salt.

[0217]¹H-NMR (δ, CDCl₃): 1.32 (m, 1H), 1.64 (m, 1H), 2.07 (m, 2H), 2.17(m, 1H), 2.70 (m, 2H), 3.06 (m, 2H), 3.31 (m, 2H), 3.55 (1, J=8, 1H),3.75 (m, 2H), 4.64 (bs, 2H, NH₂), 6.45 (d, J=8, 1H), 6.85 (d, J=7, 1H),7.16 (m, 1H), 7.2-7.6 (m, 14H), 8.10 (m, 2H).

[0218]¹³C-NMR (δ, CDCl₃): 25.7, 31.0, 31.5, 39.7, 54.0, 59.0, 60.1,68.0, 106.8, 115.2, 123.9, 125.7, 125.8, 126.1, 126.2, 126.7, 126.9,128.1, 128.6, 131.6, 132.3, 137.1, 137.7, 138.0, 143.9, 157.9, 158.2.

[0219] MS (%): 498 (parent+1, 100).

[0220] Anal. Calc'd. for C₃₅H₃₅N₃.2HCl: C 73.67, H 6.54, N 7.36. Found:C 73.86, H 6.97, N 7.04.

EXAMPLE 4

[0221]6-{4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0222] Prepared as in Example 1, in 56.5% yield, mp 172°-176° C.

[0223]¹H-NMR (δ, CDCl₃): 2.87 (m, 6H), 3.41 (m, 2H), 3.71 (m, 2H), 3.826(s, 3H), 3.831 (s, 3H), 4.60 (bs, 2H, NH₂), 6.47 (d, J=8, 1H), 6.56 (s,1H), 6.60 (s, 1H), 6.84 (d, J=7.5, 1H), 7.4-7.6 (m, 5H), 8.12 (m, 2H).

[0224]¹³C-NMR (δ, CDCl₃): 28.7, 31.3, 51.1, 55.7, 55.80, 55.83, 59.3,106.8, 109.4, 111.3, 115.15, 123.8, 125.67, 125.74, 126.0, 126.5, 126.8,131.5, 132.2, 136.8, 137.7, 138.0, 147.1, 147.4, 157.8, 158.0.

[0225] MS (%): 440 (parent+1, 100).

[0226] Anal. Calc'd. for C₂₈H₂₉N₃O₂.1/4H₂O: C 75.73, H 6.70, N 9.46.Found: C 75.66, H 6.54, N 9.17.

EXAMPLE 5

[0227]6-{4-[2-(6-Methoxy-1,3,4,9-tetrahydro-β-carbolin-2-yl)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0228] Prepared as in Example 1, in 60% yield, mp 132°-138° C.

[0229]¹H-NMR (δ, CDCl₃): 2.81 (m, 2H), 2.91 (m, 4H), 3.31 (m, 2H), 3.51(bs, 2H), 3.83 (s, 3H), 4.61 (bs, 2H, NH₂), 6.46 (d, J=8, 1H), 6.75 (dd,J=2.5,8.7, 1H), 6.84 (d, J=7, 1H), 6.92 (d, J=2.5, 1H), 7.08 (d, J=8,1H), 7.36 (d, J=7, 1H), 7.4-7.6 (m, 3H), 8.08 (d, J=8, 1H), 8.13 (dd,J=1,8, 1H), 8.39 (bs, 1H).

[0230]¹³C-NMR (δ, CDCl₃): 25.5, 50.2, 51.1, 55.8, 58.7, 67.9, 100.2,103.9, 107.8, 110.7, 111.3, 115.2, 123.8, 125.7, 125.8, 126.1, 126.6,126.8, 127.5, 131.1, 131.6, 132.1, 132.8, 136.8, 137.6, 138.1, 153.7,157.7, 158.0.

[0231] MS (%): 449 (parent+1, 100).

[0232] Anal. Calc'd. for C₂₉H₂₈N₄O.(C₄H₁₀O): C 75.83, H 7.33, N 10.72.Found: C 75.80, H 7.00, N 11.33.

EXAMPLE 6

[0233]6-(4-{2-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-ethyl}-naphthalen-1-yl)-pyridin-2-ylamine

[0234] Prepared as in Example 1, in 77% yield, mp 80°-110° C., as thehydrochloride salt.

[0235]¹H-NMR (δ, CDCl₃): 3.00 (t, J=7, 2H), 3.31 (t, J=7, 2H), 3.70 (s,2H), 4.62 (bs, 2H, NH₂), 5.90 (s, 2H), 6.48 (d, J=8, 1H), 6.72 (s, 1H),6.73 (m, 1H), 6.81 (m, 1H), 6.85 (d, J=7, 1H), 7.4-7.6 (m, 5H), 8.09 (m,2H).

[0236]¹³C-NMR (δ, CDCl₃): 33.7, 49.7, 53.7, 100.9, 106.9, 108.1, 108.7,115.2, 121.2, 123.9, 125.76, 125.80, 126.1, 126.5, 126.8, 131.7, 132.3,134.2, 136.5, 137.8, 138.1, 146.5, 147.7, 157.8, 158.1.

[0237] MS (%): 398 (parent+1, 100).

[0238] Anal. Calc'd. for C₂₅H₂₃N₃O₂.1/2HCl.H₂O.1/2(C₄H₁₀O): C 61.72, H6.14, N 8.00. Found: C 61.81, H 5.97, N 7.56.

EXAMPLE 7

[0239]6-{4-[2-(3,4-Difluoro-benzylamino)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0240] Prepared as in Example 1, in 91% yield, mp 70°-80° C., as thehydrochloride salt.

[0241]¹H-NMR (δ, CDCl₃): 2.93 (t, J=7, 2H), 3.315 (t, J=7, 2H), 3.70 (s,2H), 4.76 (bs, 2H, NH₂), 6.47 (d, J=8, 1H), 6.81 (d, J=7, 1H), 7.0-7.2(m, 3H), 7.4-7.6 (m, 5H), 8.06 (m, 2H).

[0242]¹³C-NMR (δ, CDCl₃): 32.9, 49.2, 52.2, 107.1, 115.0, 117.1, 123.7,124.2, 125.9, 126.1, 126.4, 126.7, 131.6, 132.0, 135.8, 137.8, 138.1,148.1, 148.3, 148.8, 149.0, 150.6, 150.7, 151.3, 151.4, 157.4, 158.1.

[0243] MS (%): 390 (parent+1, 100).

[0244] Anal. Calc'd. for C₂₄H₂₁N₃F₂.3/2HCl.1/2H₂O(C₄H₁₀O): C 63.78, H6.40, N 7.97. Found: C 63.94, H 5.95, N 7.89.

EXAMPLE 8

[0245]6-{4-[2-(3,4,5-Trimethoxy-benzylamino)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0246] Prepared as in Example 1, in 80% yield, mp 75°-95° C., as thehydrochloride salt.

[0247]¹H-NMR (δ, CDCl₃): 3.02 (t, J=7, 2H), 3.34 (t, J=7, 2H), 3.73 (s,2H), 3.78 (s, 6H), 3.795 (s, 3H), 4.655 (bs, 2H, NH₂), 6.46 (d, J=8,1H), 6.49 (s, 2H), 6.82 (d, J=7.5, 1H), 7.4-7.6 (m, 5H), 8.08 (m, 2H).

[0248]¹³C-NMR (δ, CDCl₃): 33.5, 49.7, 54.0, 55.9, 60.7, 104.7, 106.9,115.0, 123.8, 125.4, 125.70, 125.74, 126.1, 126.4, 126.7, 131.6, 132.1,135.8, 136.3, 136.6, 137.8, 138.0, 153.1, 157.6, 158.1.

[0249] MS (%): 444 (parent+1, 100).

[0250] Anal. Calc'd. for C₂₇H₂₉N₃O₃.2HCl.(C₄H₁₀O): C 63.05, H 7.00, N7.11. Found: C 63.04, H 6.70, N 6.96.

EXAMPLE 9

[0251]6-{4-[2-(3-Chloro-benzylamino)-ethyl]-naphthalen-1-yl}-pyridin-2-ylamine

[0252] Prepared as in Example 1, using as a precursor3,4-dichlorobenzylamine. In this case, the lithium aluminumhydride/aluminum chloride reduction removed one of the chlorine atoms,affording the 3-chlorobenzyl compound. The final product was prepared in73% yield, mp 60°-75° C., as the hydrochloride salt.

[0253]¹H-NMR (δ CDCl₃): 2.99 (t, J=7, 2H), 3.30 (t, J=7, 2H), 3.73 (bs,2H), 4.675 (bs, 2H, NH₂), 6.46 (d, J=8, 1H), 6.83 (d, J=7, 1H), 7.2-7.6(m, 9H), 8.07 (m, 2H).

[0254]¹³C-NMR (δ, CDCl₃): 33.6, 49.7, 68.0, 107.0, 115.1, 123.9, 125.8,126.1, 126.5, 126.8, 128.5, 129.5, 131.7, 132.2, 136.3, 137.8, 138.1,157.7, 158.2.

[0255] MS (%): 388 (parent+1, 100).

[0256] Anal. Calc'd. for C₂₄H₂₂N₃Cl.HCl.H₂O.1/2(C₄H₁₀O): C 65.13, H6.31, N 8.76. Found: C 64.84, H 6.25, N 8.35.

EXAMPLE 10

[0257]6-4-{2-[(Furan-2-ylmethyl)-amino]ethyl}-naphthalen-1-yl)-pyridin-2-ylamine

[0258] Prepared as in Example 1, in 44% yield, mp 185°-205° C., as thehydrochloride salt.

[0259]¹H-NMR (δ, CDCl₃): 3.00 (d, J=7, 2H), 3.295 (d, J=7, 2H), 3.79 (s,2H), 4.68 (bs, 2H, NH₂), 6.13 (bs, 1H), 6.26 (bs, 1H), 6.45 (d, J=8,1H), 6.83 (d, J=7.5, 1H), 7.3-7.6 (m, 6H), 8.08 (m, 2H).

[0260]¹³C-NMR (δ, CDCl₃): 33.4, 46.1, 49.5, 106.9, 107.0, 110.0, 115.05,123.8, 125.7, 126.0, 126.4, 126.7, 131.6, 132.1, 136.2, 137.7, 138.0,141.75, 153.5, 157,6, 158.1.

[0261] MS (%): 344 (parent+1, 100).

[0262] Anal. Calc'd. for C₂₂H₂₁N₃O.HCl.3/2H₂O: C 64.23, H 6.25, N 10.21.Found: C 64.42, H 6.04, N 9.86.

EXAMPLE 11

[0263]6-{4-[2-(3,4-Dichloro-benzylamino)-ethyl]-naphthalen-1-yl}pyridin-2-ylamine

[0264] Prepared as in Example 1, using borane methyl sulfide in place ofthe lithium aluminum hydride/aluminum chloride reduction in the finalstep. The final product was prepared in 68.5% yield, mp 145°-170° C., asthe hydrochloride salt.

[0265]¹H-NMR (δ, CDCl₃): 2.98 (t, J=7, 2H), 3.295 (t, J=7, 2H), 3.71 (s,2H), 4.60 (bs, 2H, NH₂), 6.49 (d, J=8, 1H), 6.85 (d, J=7.5, 1H), 7.2-7.6(m, 7H), 8.08 (m, 2H).

[0266]¹³C-NMR (δ, CDCl₃): 33.6, 49,7, 52.7, 107.0, 115.3, 123.8, 125.8,125.9, 126.2, 126.5, 126.9, 127.3, 127.4, 129.9, 130.0, 130.2, 130.7,131.7, 132.2, 132.3, 136.2, 138.1, 140.7, 157.8, 158.1.

[0267] MS (%): 388 (parent+1, 100).

[0268] Anal. Calc'd. for C₂₄H₂₁N₃Cl₂.HCl.2H₂O.1/2(C₄H₁₀O): C 58.71, H5.87, N 7.90. Found: C 58.35, H 5.92, N 6.62.

EXAMPLE 12

[0269] 6-[4-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0270] Referring to Scheme 2

[0271] A. 4-Bromo-1-benzyloxy-naphthalene

[0272] To a 250 mL round-bottomed flask equipped with addition funneland N₂ inlet were added 2.88 g (20 mmol) 1-naphthol and 50 mL1,2dichloroethane, and with stirring a solution of 9.64 g (20 mmol)tetrabutylammonium tribromide in 30 mL 1,2-dichloroethane dropwise over10 minutes. After stirring an additional 10 minutes at room temperature,the solution was washed with dilute aqueous sodium bisulfite and water,dried over sodium sulfate, and evaporated. The mixture of product andtributylammonium salts was used directly.

[0273]¹H-NMR (δ, CDCl₃): 7.22 (d, J=8, 1H), 7.43 (m, 2H), 7.50 (dt,J=1,8, 1H), 8.05 (d, J=8, 1H), 8.18 (d, J=8, 1H).

[0274]¹³C-NMR (δ, CDCl₃): 109.8, 111.4, 122.7, 125.3, 126.25, 126.7,137.4, 129.9, 132.5, 153.0.

[0275] The above oil was dissolved in 100 mL acetonitrile, and treatedwith 3.57 mL (30 mmol) benzyl bromide and 5.53 g (40 mmol) potassiumcarbonate, the refluxed 14 hours. TLC showed a major spot at R_(f)=0.2in 5% methylene chloride/hexane. The reaction was cooled, poured intodilute aqueous hydrochloric acid/ethyl acetate, and the organic layerseparated, washed with water and brine, dried over sodium sulfate, andevaporated. The residue was chromatographed on silica gel usingmethylene chloride/hexane as eluant to afford 5.8 g (93%) of an oil.

[0276]¹H-NMR (δ, CDCl₃): 5.22 (s, 2H), 6.74 (d, J=8, 1H), 7.4-7.7 (m,8H), 8.21 (d, J=8, 1H), 8.39 (d, J=8, 1H).

[0277]¹³C-NMR (δ, CDCl₃): 70.3, 105.9, 113.6, 122.7, 126.1, 126.9,127.0, 127.4, 127.9, 128.1, 128.7, 129.5, 132.6, 136.7, 154.3.

[0278] MS (%): 314 (parent+1, 100).

[0279] B. 1-Benzyloxy-naphthalene-4-boronic Acid

[0280] Using the procedure in Example 1A, 5.95 g (19 mmol) of4-bromo-1-benzyloxy-naphthalene was converted to the product in 55%yield as a white solid, mp 149°-152° C.

[0281]¹H-NMR (δ, CDCl₃): 5.18 (s, 2H), 6.82 (m, 1H), 7.2-7.8 (m, 8H),8.28 (m, 2H).

[0282]¹³C-NMR (δ, CDCl₃): 69.9, 104.5, 104.7, 122.2, 122.4, 124.8,125.0, 126.5, 126.6, 127.6, 127.7, 127.9, 128.0, 128.5, 130.9, 132.9,136.9.

[0283] C. 2-(2,5-Dimethylpyrrolyl)-6-(4-benzyloxy-1-naphthyl)-pyridine

[0284] Prepared as in Example 1B, in ˜100% yield as an oil.

[0285]¹H-NMR (δ, CDCl₃): 2.25 (s, 6H), 5.29 (s, 2H), 5.92 (S, 2H), 6.95(d, J=8, 1H), 7.21 (d, J=7.5, 1H), 7.3-7.6 (m, 9H), 7.89 (t, J=8, 1H),8.14 (m, 1H), 8.45 (m, 1H).

[0286]¹³C-NMR (δ, CDCl₃): 13.5, 70.1, 104.8, 106.8, 119.7, 122.5, 123.4,125.2, 125.3, 125.9, 126.4, 126.9, 127.3, 127.9, 128.2, 128.6, 130.5,132.0, 136.9, 138.0, 151.8, 155.0, 159.1.

[0287] MS (%): 405 (parent+1, 100).

[0288] D. 2-(2,5-Dimethylpyrrolyl)-6-(4hydroxy-1-naphthyl)-pyridine

[0289] To a 125 mL round-bottomed flask equipped with condenser and N₂inlet were added 1.53 g (3.795 mmol)2-(2,5-dimethylpyrrolyl)-6-(4-benzyloxy-1-naphthyl)-pyridine, 1.20 g(18.975 mmol) ammonium formate, 100 mg 10% palladium-on-carbon, and 30mL ethanol. The reaction was refluxed 4 hours, with additional catalystand formate added at 2 and 3 hours, then cooled and filtered throughCelite with ethanol and methylene chloride. The filtrate was evaporatedand the residue taken up in ethyl acetate/aqueous sodium bicarbonatesolution. The organic layer was washed with brine, dried over sodiumsulfate, and evaporated to a light brown solid, 1.21 g (˜100%).

[0290]¹H-NMR (δ, CDCl₃): 2.105 (s, 6H), 5.775 (s, 2H), 6.66 (d, J=8,1H), 7.04 (d, J=8, 1H), 7.29 (m, 2H), 7.38 (d, J=8, 1H), 7.72 (t, J=8,1H), 7.95 (m, 1H), 8.18 (m, 1H).

[0291]¹³C-NMR (δ, CDCl₃): 13.8, 106.7, 106.8, 107.6, 119.6, 122.55,124.5, 124.7, 125.0, 126.5, 128.4, 128.5, 128.7, 132.0, 138.2, 151.5,153.9, 159.3.

[0292] MS (%): 315 (parent+1, 100).

[0293] E.2-(2,5-Dimethylpyrrolyl)-6-(4-(2-carboethoxymethyloxy)-1-naphthyl)-pyridine

[0294] To a 125 mL round-bottomed flask equipped with condenser and N₂inlet were added 1.19 g (3.795 mmol)2-(2,5-dimethylpyrrolyl)-6-(4-hydroxy-1-naphthyl)-pyridine, 0.505 mL(4.554 mmol) ethyl bromoacetate, 1.05 g (7.59 mmol) potassium carbonate,and 25 mL acetonitrile. The mixture was refluxed 12 hours, cooled (TLCRf=0.6 in 1/1-ethyl acetate/hexane), poured into water, and extractedinto ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated. The residue was chromatographed onsilica gel using hexane/ethyl acetate as eluant to afford 2.05 g (˜100%)of an oil.

[0295]¹H-NMR (δ, CDCl₃): 1.31 (t, J=7, 3H), 2.26 (s, 6H), 4.29 (q, J=7,2H), 4.82 (s, 2H), 5.94 (s, 2H), 6.78 (d, J=8, 1H), 7.20 (d, J=8, 1H),7.5-7.6 (m, 5H), 7.87 (t, J=8, 1H), 8.15 (m, 1H), 8.50 (m, 1H).

[0296]¹³C-NMR (δ, CDCl₃): 13.6, 14.2, 61.4, 65.7, 104.6, 107.0, 119.9,122.6, 123.6, 125.3, 125.6, 125.8, 127.2, 128.0, 128.6, 131.4, 132.1,138.3, 151.8, 154.3, 158.9, 168.6.

[0297] MS (%): 401 (parent+1, 100).

[0298] F.2-(2,5-Dimethylpyrrolyl)-4-(4-(2-carboxymethyloxy)-1-naphthyl)-pyridine

[0299] To a 125 mL round-bottomed flask equipped with condenser and N₂inlet were added 1.52 g (3.795 mmol) of2-(2,5-dimethylpyrrolyl)-6-(4-(2-carboethoxymethyloxy)-1-naphthyl)-pyridine,15 mL tetrahydrofuran, and 478 mg (11.385 mmol) lithium hydroxidehydrate in 15 mL water, with additional methanol to maintain a solution.The reaction was stirred at room temperature for 12 hours, (LCMSP+1=373), poured into dilute aqueous hydrochloric acid, and extractedinto ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated to a solid, 1.27 g (90%).

[0300]¹H-NMR (δ, CDCl₃): 2.20 (s, 6H), 4.74 (s, 2H), 5.89 (s, 2H), 6.765(d, J=8, 1H), 7.20 (d, J=8, 1H), 7.4-7.6 (m, 4H), 7.885 (t, J=8, 1H),8.04 (m, 1H), 8.44 (m, 1H).

[0301]¹³C-NMR (δ, CDCl₃): 13.3, 65.3, 104.5, 106.9, 120.3, 122.6, 124.0,125.0, 125.6, 125.7, 127.2, 128.0, 128.7, 130.8, 132.0, 138.6, 151.7,154.3, 158.9, 170.9.

[0302] MS (%): 373 (parent+1, 100).

[0303] G.2-(2,5-Dimethylpyrrolyl)-6-(4-(2-(dimethylaminocarbonyl)methyloxy)-1-naphthyl)-pyridine

[0304] Prepared as in Example 1D in ˜100% yield as an oil.

[0305]¹H-NMR (δ, CDCl₃): 2.225 (s, 6H), 2.97 (s, 3H), 3.10 (s, 3H), 4.90(s, 2H), 5.89 (s, 2H), 6.93 (d, J=8, 1H), 7.21 (d, J=8, 1H), 7.4-7.6 (m,4H), 7.90 (t, J=8, 1H), 8.09 (m, 1H), 8.38 (m, 1H).

[0306]¹³C-NMR (δ, CDCl₃): 13.5, 35.8, 36.8, 67.9, 104.7, 106.8, 119.9,122.2, 123.5, 125.4, 125.56, 125.63, 127.1, 128.1, 128.6, 131.2, 132.1,138.2, 151.8, 154.1, 159.0, 167.7.

[0307] MS (%): 400 (parent+1, 100).

[0308] H.2-(2,5-Dimethylpyrrolyl)-6-(4-(2-(2-dimethylaminoethyl)methyloxy)-1-naphthyl)-pyridine

[0309] Prepared as in Example 1E in ˜100% yield as an oil.

[0310]¹H-NMR (δ, CDCl₃): 2.24 (s, 6H), 2.42 (s, 6H), 2.915 (t, J=6, 2H),4.30 (t, J=6, 2H), 5.91 (s, 2H), 6.90 (d, J=8, 1H), 7.20 (d, J=8, 1H),7.5-7.7 (m, 4H), 7.89 (t, J=8, 1H), 8.13 (m, 1H), 8.37 (m, ₁H).

[0311]¹³C-NMR (δ, CDCl₃): 13.5, 46.2, 58.2, 67.0, 104.3, 106.8, 119.7,122.5, 123.5, 125.2, 125.3, 123.8, 126.9, 128.3, 138.6, 130.4, 132.0,138.1, 151.8, 155.3, 159.1.

[0312] MS (%): 386 (parent+1, 100).

[0313] I.6-[4-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0314] To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 155 mg (0.403 mmol)2-(2,5-dimethylpyrrolyl)-6-(4-(2-(2-dimethylaminoethyl)methyloxy)-1-naphthyl)-pyridine,500 mg hydroxylamine hydrochloride, 9 mL ethanol, and 1 mL water. Thesolution was refluxed 40 h (LCMS P+1=308), cooled, poured into diluteaqueous hydrochloric acid, and washed with ethyl acetate. The aqueouslayer was adjusted to pH 12 with 6N aqueous sodium hydroxide solutionand extracted with several portions of methylene chloride. The organiclayer was dried over sodium sulfate and evaporated to a solid, 81 mg(65%), mp 98°-106° C.

[0315]¹H-NMR (δ, CDCl₃): 2.395 (s, 6H), 2.89 (t, J=6, 2H), 4.27 (t, J=6,2H), 4.65 (bs, 2H, NH₂), 6.43 (d, J=8, 1H), 6.84 (m, 2H), 7.4-7.6 (m,4H), 8.10 (m, 1H), 8.32 (m, 1H).

[0316]¹³C-NMR (δ, CDCl₃): 46.2, 58.2, 66.9, 104.2, 106.6, 115.2, 122.2,125.1, 125.7, 125.8, 126.7, 127.2, 131.4, 132.2, 138.0, 154.7, 157.8,158.2.

[0317] MS (%): 308 (parent+1, 100).

[0318] Anal. Calc'd. for C₁₉H₂₁N₃O.1/4H₂O: C 73.17, H 6.95, N 13.47.Found: C 73.18, H 7.00, N 13.43.

EXAMPLE 13

[0319] 6-4-(2-Pyrrolidin-1-yl-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0320] Prepared as in Example 12, in 69% yield, mp 245°-255° C., as thehydrochloride salt.

[0321]¹H-NMR (δ, CDCl₃): 1.79 (bs, 4H), 2.685 (bs, 2H), 3.035 (t, J=6,2H), 4.30 (t, J=6, 2H), 4.68 (bs, 2H, NH₂), 6.41 (d, J=8, 1H), 6.82 (m,2H), 7.4-7.6 (m, 4H), 8.10 (m, 1H), 8.31 (m, 1H).

[0322]¹³C-NMR (δ, CDCl₃): 23.6, 54.9, 55.0, 67.8, 104.2, 106.6, 115.1,122.2, 125.0, 125.7, 125.8, 126.6, 127.3, 131.4, 132.2, 138.0, 154.7,157.7, 158.2.

[0323] MS (%): 334 (parent+1, 100).

[0324] Anal. Calc'd. for C₂₁H₂₃N₃O.2HCl.1/2(C₄H₁₀O): C 63.30, H 6.82, N9.48. Found: C 62.23, H 6.41, N 9.56.

EXAMPLE 14

[0325]6-(4-{2-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-ethoxy}-naphthalen-1-yl)-pyridin-2-ylamine

[0326] Prepared as in Example 12, in 75% yield, mp 60°-80° C., as thehydrochloride salt.

[0327]¹H-NMR (δ, CDCl₃): 3.12 (t, J=6, 2H), 3.81 (s, 2H), 4.25 (t, J=6,2H), 5.91 (s, 2H), 6.41 (d, J=8, 1H), 6.7-6.8 (m, 4H), 6.89 (s, 1H),7.4-7.5 (m, 4H), 8.10 (m, 1H), 8.28 (m, 1H).

[0328]¹³C-NMR (δ, CDCl₃): 47.9, 53.5, 67.7, 100.9, 104.4, 106.6, 108.1,108.7, 115.1, 121.3, 122.0, 125.1, 125.7, 125.8, 126.7, 127.3, 131.5,132.2, 134,1, 138.0, 146.6, 147.8, 154.6, 157.6, 158.3.

[0329] MS (%): 414 (parent+1, 100).

[0330] Anal. Calc'd. for C₂₅H₂₃N₃O₃.HCl.3/2H₂O: C 62.96, H 5.71, N 8.81.Found: C 63.17, H 5.63, N 8.48.

EXAMPLE 15

[0331]6-{4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine

[0332] Prepared as in Example 12, in 61% yield, mp 130°-150° C., as thehydrochloride salt.

[0333]¹H-NMR (δ, CDCl₃): 2.83 (m, 2H), 2.90 (m, 2H), 3.105 (t, J=6, 2H),3.74 (s, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 4.37 (t, J=6, 2H), 4.69 (bs,2H, NH₂), 6.39 (d, J=8, 1H), 6.49 (s, 1H), 6.57 (s, 1H), 6.84 (m, 2H),7.4-7.5 (m, 4H), 8.11 (m, 1H), 8.33 (m, 1H).

[0334]¹³C-NMR (δ, CDCl₃): 28.6, 51.6, 55.9, 56.1, 56.8, 67.0, 104.3,106.6, 109.5, 111.3, 115.1, 122.2, 125.1, 125.7, 125.8, 125.9, 126.4,126.7, 127.3, 147.2, 147.5, 154.6, 157.6, 158.2.

[0335] MS (%): 456 (parent+1, 100).

[0336] Anal. Calc'd. for C₂₈H₂₉N₃O₃.2HCl.H₂O: C 61.54, H 6.09, N 7.69.Found: C 61.77, H 6.04, N 7.35.

EXAMPLE 16

[0337]3-{2-[4-(6-Amino-pyridin-2-yl)-naphthalen-1-yloxy]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine

[0338] Prepared as in Example 12, in 63% yield (following a deblockingstep with trifluoroacetic acid in methylene chloride to remove at-butoxycarbonyl protecting group), mp 140°-155° C., as thehydrochloride salt.

[0339]¹H-NMR (3, CDCl₃): 1.35 (bs, 2H), 1.41 (s, 1H), 2.53 (bs, 2H),2.93 (t, J=6, 2H), 3.11 (m, 4H), 4.185 (t, J=6, 2H), 4.67 (bs, 2H, NH₂),6.42 (d, J=8, 1H), 6.81 (m, 2H), 7.4-7.5 (m, 4H), 8.10 (m, 1H), 8.29 (m,1H).

[0340]¹³C-NMR (δ, CDCl₃): 25.8, 32.6, 54.0, 55.6, 67.7, 104.2, 106.6,115.2, 122.2, 125.1, 125.7, 125.9, 126.6, 127.3, 132.1, 133.7, 138.0,154.7, 157.7, 158.2.

[0341] MS (%): 361 (parent+1, 100).

[0342] Anal. Calc'd. for C₂₂H₂₄N₄O.2HCl.1/2(C₄H₁₀O): C 61.28, H 6.64, N11.91. Found: C 61.89, H 6.44, N 11.83.

EXAMPLE 17

[0343]6-{4-[2-(4-Phenethyl-piperazin-1-yl}-ethoxy]-naphthalen-1-yl)-pyridin-2-ylamine

[0344] Prepared as in Example 12, in 78% yield, mp 45°-80° C., as thehydrochloride salt.

[0345]¹H-NMR (δ, CDCl₃): 2.5-2.9 (m, 12H), 3.00 (t, J=6, 2H), 4.325 (t,J=6, 2H), 4.62 (bs, 2H), 6.47 (d, J=8, 1H), 6.84 (d, J=8, 1H), 6.85 (d,J=7, 1H), 7.20 (m, 3H), 7.28 (m, 2H), 7.46 (m, 4H), 8.10 (m, 1H), 8.31(m, 1H).

[0346]¹³C-NMR (δ, CDCl₃): 33.53, 53.14, 53.64, 57.135, 60.43, 66.61,104.26, 106.49, 115.165, 122.10, 125.04, 125.43, 125.61, 125.94, 126.57,127,15, 128.29, 128.61, 131.41, 132.40, 137.92, 140.23, 154.61, 157.67,158.03.

[0347] MS (%): 453 (parent+1, 100).

[0348] Anal. Calc'd. for C₂₉H₃₂N₄O.3HCl.3/2H₂O.(C₄H₁₀O): C 59.77, H7.30, N 8.45. Found: C 59.42, H 7.19, N 8.05.

EXAMPLE 18

[0349]6-{4-[2-(3-Amino-pyrrolidin-1-yl}-ethoxy]-naphthalen-1-yl)-pyridin-2-ylamine

[0350] Prepared as in Example 12, in 59% yield, mp 70°-90° C., as thehydrochloride salt.

[0351]¹H-NMR (δ, CDCl₃): 1.25 (m, 2H), 2.5 (m, 1H), 2.6 (m, 1H), 2.88(m, 2H), 3.035 (t, J=6, 2H), 4.30 (t, J=6, 2H), 4.59 (bs, 2H), 6.47 (d,J=8, 1H), 6.85 (m, 2H), 7.4-7.6 (m, 4H), 8.09 (m, 1H), 8.31 (m, 1H).

[0352]¹³C-NMR (δ, CDCl₃): 35.14, 50.90, 53.95, 54.71, 64.63, 67.60,104.19, 106.45, 115.21, 122.12, 125.00, 125.60, 126.54, 126.72, 127.16,137.92, 142.45, 147.38, 154.66, 156.33, 157.92.

[0353] MS (%): 349 (parent+1, 100).

[0354] Anal. Calc'd. for C₂₁H₂₄N₄O.2HCl.2(C₄H₁₀O).1/3(CH₂Cl₂): C 58.92,H 7.87, N 9.37. Found: C 58.93, H 7.84, N 7.77.

EXAMPLE 19

[0355]6-[4-2-Diisopropylamino-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0356] Prepared as in Example 12, in 97.5% yield, as an amorphous solid.

[0357]¹H-NMR (δ, CDCl₃): 1.09 (d, J=6.6, 12H), 3.01 (t, J=7, 2H), 3.11(m, 2H), 4.12 (t, J=7, 2H), 4.62 (bs, 2H), 6.43 (d, J=8, 1H), 6.86 (m,2H), 7.47 (m, 4H), 8.14 (m, 1H), 8.35 (m, 1H).

[0358]¹³C-NMR (δ, CDCl₃): 20.94, 44.49, 49.61, 69.61, 104.27, 106.50,115.22, 124.97, 125.70, 125.86, 126.59, 127.34, 131.20, 132.17, 137.98,154.93, 157,90, 158.14.

[0359] MS (%): 364 (parent+1, 100).

[0360] HRMS Calc'd. for C₂₃H₃₀N₃O: 364.2389. Found: 364.2383.

EXAMPLE 20

[0361] 6-[4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0362] Prepared as in Example 12, in 60% yield, as an amorphous solid.

[0363]¹H-NMR (δ, CDCl₃): 2.66 (m, 4H), 2.96 (t, J=6, 2H), 3.74 (m, 4H),4.32 (t, J=6, 2H), 4.60 (bs, 2H), 6.48 (d, J=8, 1H), 6.86 (m, 2H), 7.46(m, 4H), 8.11 (m, 1H), 8.30 (m, 1H).

[0364]¹³C-NMR (δ, CDCl₃): 54.10, 57.55, 66.54, 66.94, 104.32, 106.49,115.19, 122.02, 125.07, 125.61, 125.78, 126.60, 127.13, 131.42, 132.10,137.97, 154.56, 157.59, 157.93.

[0365] MS (%): 350 (parent+1, 100).

[0366] Anal. Calc'd. for C₂₁H₂₃N₃O₂.1/4H₂O: C 72.18, H 6.63, N 12.03.Found: C 71.62, H 6.67, N 11.69.

EXAMPLE 21

[0367] 6-[4-(2-Piperidin-1-yl-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0368] Prepared as in Example 12, in 68% yield, as an amorphous solid asthe hydrochloride salt.

[0369]¹H-NMR (δ, CDCl₃): 1.45 (m, 2H), 1.60 (m, 4H), 2.58 (m, 4H), 2.93(t, J=6, 2H), 4.30 (t, J=6, 2H), 4.66 (bs, 2H), 6.38 (d, J=8, 1H), 6.82(m, 2H), 7.45 (m, 4H), 8.11 (m, 1H), 8.32 (m, 1H).

[0370]¹³C-NMR (δ, CDCl₃): 24.19, 26.07, 55.08, 57.91, 66.66, 104.33,106.54, 115.09, 122.22, 125.07, 125.75, 125.86, 126.62, 127.18, 131.46,132.17, 137.94, 154.71, 157.75, 158.24.

[0371] MS (%): 348 (parent+1, 100).

[0372] Anal. Calc'd. for C₂₂H₂₅N₃O.2HCl.3H₂O.1/4(C₄H₁₀O): C 56.04, H7.26, N 8.52. Found: C 56.20, H 7.11, N 8.27.

EXAMPLE 22

[0373]6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine

[0374] Prepared as in Example 12, in 26% yield, as an amorphous solid asthe hydrochloride salt.

[0375]¹H-NMR (δ, CDCl₃): 2.96 (m, 4H), 3.16 (t, J=6, 2H), 3.87 (m, 2H),4.42 (t, J=6, 2H), 4.58 (bs, 2H), 6.48 (d, J=8, 1H), 6.88 (m, 2H), 7.01(m, 1H), 7.11 (m, 3H), 7.50 (m, 4H), 8.12 (m, 1H), 8.36 (m, 1H).

[0376]¹³C-NMR (δ, CDCl₃): 28.96, 51.46, 56.43, 56.79, 66.94, 104.34,106.45, 115.21, 122.10, 125.04, 125.57, 125.64, 125.84, 126.11, 126.52,126.57, 127.16, 128.61, 131.46, 132.13, 133.98, 134.48, 137.92, 154.63,157.73, 157.96.

[0377] MS (%): 396 (parent+1, 100).

[0378] HRMS Calc'd. for C₂₆H₂₆N₃O: 396.2076. Found: 396.2080.

EXAMPLE 23

[0379]6-{4-[2-(4-Dimethylamino-piperidin-1-yl)-ethoxy]-naphthalen-1-yl}pyridin-2-ylamine

[0380] Prepared as in Example 12, in 73% yield, as an amorphous solid asthe hydrochloride salt.

[0381]¹H-NMR (δ, CDCl₃): 1.56 (m, 2H), 1.80 (m, 2H), 2.18 (m, 3H), 2.26(s, 6H), 4.28 (t, J=6, 2H), 3.10 (m, 2H), 4.28 (t, J=6, 2H), 4.58 (bs,2h), 6.43 (d, J=8, 1H), 6.83 (m, 2H), 7.44 (m, 4H), 8.09 (m, 1H), 8.29(m, ₁H).

[0382]¹³C-NMR (δ, CDCl₃): 28.33, 29.70, 41.61, 53.65, 57.12, 62.11,66.77, 76.76, 104.33, 106.51, 115.22, 122.15, 125.09, 125.70, 125.85,126.64, 127.23, 131.49, 132.15, 137.97, 154.65, 157.80, 158.08.

[0383] MS (%): 391 (parent+1, 100).

[0384] Anal. Calc'd. for C₂₄H₃₀N₄O.3HCl.3H₂O.1/2(C₄H₁₀O): C 52.84, H7.50, N 9.48. Found: C 52.65, H 7.78, N 9.38.

[0385] HRMS Calc'd. for C₂₄H₃₁N₄O: 391.2498. Found: 391.2485.

EXAMPLE 24

[0386]6-[4-(1-Benzyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0387] A. 4-Bromo-1-fluoronaphthalene

[0388] To a 50 mL round-bottomed flask equipped with condenser and N₂inlet were added 3.75 mL (5.0 g, 34.25 mmol) 1-fluoronaphthalene and 10mL carbon tetrachloride, followed by dropwise addition of 1.7 mL (5.5g., 34.375 mmol) bromine over 3 min. The reaction was heated to 50°-60°C. as HBr was evolved for 2 hours, then cooled and concentrated. Theresidue was dissolved in methanol and kept overnight at 0° C. Afterfiltration with cold methanol, the product, with mp close to roomtemperature, was 4.62 g (60%) of a yellow oil.

[0389]¹H-NMR (δ, CDCl₃): 7.02 (t, J=8, 1H), 7.6-7.7 (m, 3H), 8.10 (d,J=8.5, 1H), 8.20 (d, J=8.5, 1H).

[0390] GCMS (%): 224/226 (parent, Br⁷⁹/Be⁸¹ 100).

[0391] B. 4-Fluoronaphthalene-1-boronic Acid

[0392] To a 250 mL three-necked round-bottomed flask equipped withseptum and N₂ inlet were added 4.62 g (20.53 mmol)4-bromo-1-fluoronaphthalene and 100 mL dry tetrahydrofuran. The solutionwas cooled to −70° C., and 15.4 mL (24.64 mmol) of a 1.6M solution ofbutyl lithium in hexane was added dropwise over 5 min. The reaction wasstirred at −70° C. for 10 min, then 4.2 mL (3.59 g, 24.64 mmol) triethylborate was added, and the reaction stirred at −70° C. for 20 min andwarmed to room temperature. After stirring overnight at roomtemperature, the reaction was quenched with saturated aqueous ammoniumchloride solution, acidified with 1N hydrochloric acid, and extractedinto ethyl acetate (twice). The combined organic layer was washed withbrine, dried over sodium sulfate, and evaporated. The residue wastriturated with hexane to give an off-white powder, 1.97 g (51%), as amixture of monoaryl and diaryl boronic acids.

[0393]¹H-NMR (δ, CDCl₃): 7.2-7.4 (m, 1H), 7.5-7.7 (m, 3H), 8.0-8.5 (m,1H), 8.5 and 9.2 (m, 1H).

[0394] APCI (−) (%): 189 (parent-1, 60).

[0395] C. 2-(2,5-Dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine

[0396] To a 50 mL round-bottomed flask equipped with condenser and N₂inlet were added 404 mg (2.13 mmol) 4-fluoronaphthalene-1-boronic acid,534 mg (2.13 mmol) 2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg(8.51 mmol) sodium carbonate, 150 mg tetrakistriphenylphosphine, 10 mLethanol, and 2 mL water. The reaction was refluxed overnight, cooled,poured into water, and extracted into ethyl acetate. After combiningwith another run on a larger scale, the combined organic layer waswashed with brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using hexane/ethyl acetate aseluant to afford 4.72 g (85%) of an oil.

[0397]¹H-NMR (δ, CDCl₃): 2.25 (s, 6H), 5.92 (s, 2H), 7.1-7.2 (m, 2H),7.4-7.6 (m, 4H), 7.95 (t, J=8, 1H), 8.12 (d, J=8, 1H), 8.19 (d, J=8,1H).

[0398]¹³C-NMR (δ, CDCl₃): 13.41, 106.97, 108.82, 109.02, 120.18, 120.78,120.84, 123.42, 123.81, 123.96, 125.48, 126.20, 127.32, 127.68, 127.76,128.56, 132.35, 133.90, 138.22, 151.87, 157.82, 158.30, 160.34.

[0399] MS (%): 317 (parent+1, 100).

[0400] HRMS Calc'd. for C₂₁H₁₈N₂F (parent+1): 317.1454. Found: 317.1462.

[0401] D.2-(2,5-Dimethylpyrrolyl)-6(4-((N-benzyl)-4-piperidinyloxy)-naphth-1-yl)pyridine

[0402] To a 20 mL round-bottomed flask equipped with condenser and N₂inlet were added 121 mg (0.633 mml) 4-hydroxy-N-benzylpiperidine and 5mL dry dimethylformamide, followed by 32 mg (0.791 mmol) sodium hydride(60% in oil). The reaction was heated to 70° C. to ensure completeformation of the alkoxide, and then 100 mg (0.316 mmol)2-(2,5-dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine in 2 mL drydimethylformamide was added, and the reaction was heated at 80° C. for10 min. The reaction was cooled, poured into water, and extracted intoethyl acetate. After combining with another run on a larger scale, thecombined organic layer was washed with brine, dried over sodium sulfate,and evaporated. The residue was chromatographed on silica gel usingmethanol/methylene chloride as eluant to afford 489 mg (54%) of an oil.

[0403]¹H-NMR (δ, CDCl₃): 2.04 (m, 2H), 2.10 (m, 2H), 2.25 (s, 6H), 2.44(m, 2H), 2.79 (m, 2H), 3.58 (s, 2H), 4.65 (m, 1H), 5.91 (s, 2H), 6.92(d, J=8, 1H), 7.2-7.6 (m, 7H), 7.90 (t, J=8, 1H), 8.12 (m, 1H), 8.39 (m,1H).

[0404]¹³C-NMR (δ, CDCl₃): 13.55, 30.69, 50.43, 63.19, 72.54, 105.94,106.84, 119.72, 122.68, 123.50, 125.22, 126.69, 126.90, 127.08, 128.27,128.32, 128.67, 129.09, 129.19, 130.12, 132.22, 138.09, 138.40, 151.83,153.75, 159.16.

[0405] MS (%): 488 (parent+1, 100).

[0406] HRMS Calc'd. for C₃₃H₃₄N₃O (parent+1): 488.2702. Found: 488.2703.

[0407] E.6-[4-(1-Benzyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0408] Prepared as in Example 12I, in 93% yield, mp 265°-285° C. (dec.),as the hydrochloride salt.

[0409]¹H-NMR (δ, CDCl₃): 1.9-2.1 (m, 4H), 2.41 (m, 2H), 2.77 (m, 2H),4.61 (m, 1H), 4.68 (bs, 2H, NH), 6.42 (d, J=8, 1H), 6.86 (m, 2H),7.2-7.5 (m, 9H), 8.12 (m, 1H), 8.37 (m, 1H).

[0410]¹³C-NMR (δ, CDCl₃): 30.65, 50.37, 63.10, 72.53, 106.05, 106.49,115.08, 122.37, 124.97, 125.67, 126.52, 126.70, 126.97, 127.12, 128.16,129.11, 131.24, 132.38, 137.89, 138.35, 153.16, 157.66, 158.16.

[0411] MS (%): 410 (parent+1, 100).

[0412] Anal. Calc'd. for C₂₇H₂₇N₃O.2HCl.5/3H₂O: C 63.28, H 6.36, N 8.20.Found: C 63.18, H 6.40, N 7.88.

EXAMPLE 25

[0413]6-[4-(1-Benzyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0414] Prepared as in Example 24, in 98% yield, mp 160°-170° C., as thehydrochloride salt.

[0415]¹H-NMR (δ, CDCl₃): 2.15 (m, 1H), 2.36 (m, 1H), 2.67 (m, 1H), 2.79(m, 1H), 2.87 (m, 1H), 3.12 (m, 1H), 3.69 (AB_(q), J=13, Dn=20, 2H),4.74 (bs, 2H), 5.00 (m, 1H), 6.37 (d, J=8, 1H), 6.72 (d, J=8, 1H), 6.83(d, J=8, 1H), 7.2-7.6 (m, 9H), 8.14 (m, 1H), 8.38 (m, 1H).

[0416]¹³C-NMR (δ, CDCl₃): 32.37, 52.84, 60.17, 60.35, 77.0, 105.32,106.52, 114.95, 122.40, 125.02, 125.70, 126.11, 126.62, 127.03, 127.12,128.28, 128.82, 131.33, 132.28, 137.88, 138.70, 153.59, 157.59, 158.26.

[0417] MS (%): 396 (parent+1, 100).

[0418] Anal. Calc'd. for C₂₆H₂₅N₃O.2HCl.5/3H₂O: C 62.65, H 6.13, N 8.43.Found: C 62.73, H 6.06, N 8.40.

EXAMPLE 26

[0419] 6-[4-(4-Dimethylamino-butoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0420] Prepared as in Example 24, in 71% yield, mp 78°-90° C., as thehydrochloride salt.

[0421]¹H-NMR (δ, CDCl₃): 1.75 (m, 2H), 1.94 (m, 2H), 2.23 (s, 6H), 2.37(m, 2H), 4.16 (t, J=6, 2H), 4.63 (bs, 2H), 6.43 (d, J=8, 1H), 6.83 (m,2H), 7.4-7.6 (m, 4H), 8.08 (m, 1H), 8.32 (m, 1H).

[0422]¹³C-NMR (δ, CDCl₃): 24.33, 27.12, 45.31, 59.34, 67.90, 104.06,106.44, 115.11, 122.09, 124.91, 125.57, 125.83, 126.49, 127.17, 131.12,132.08, 137.88, 154.86, 157.73, 158.06.

[0423] MS (%): 336 (parent+1, 100).

[0424] Anal. Calc'd. for C₂₁H₂₅N₃O.2HCl.1/2(H₂CO₃).5/4H₂O: C 55.91, H6.66, N 9.10. Found: C 55.89, H 6.89, N 8.80.

EXAMPLE 27

[0425] 6-[4-(Piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0426] Prepared as in Example 24, in 88% yield, mp 65°-75° C. as thefree base, and mp 205°-220° C., as the hydrochloride salt.

[0427]¹H-NMR (δ, CDCl₃): 1.80 (m, 2H), 2.01 (m, 2H), 2.72 (m, 2H), 3.12(m, 2H), 4.59 (m, 1H), 4.71 (bs, 2H), 6.38 (d, J=8, 1H), 6.82 (m, 2H),7.4-7.6 (m, 4H), 8.10 (m, 1H), 8.34 (m, 1H).

[0428]¹³C-NMR (δ, CDCl₃): 32.01, 43.63, 73.20, 106.09, 106.44, 114.95,122.30, 124.94, 125.66, 126.49, 126.67, 127.05, 131.32, 132.35, 137.84,153.03, 157.64, 158.19.

[0429] MS (%): 320 (parent+1, 100).

[0430] Anal. Calc'd. for C₂₀H₂₁N₃O.3/4(C₄H₈O₂).1/2H₂O: C 70.03, H 7.15,N 10.65. Found: C 70.30, H 6.77, N 10.99.

EXAMPLE 28

[0431] 6-[4-(Pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine:Prepared as in Example 24, in 75% yield, mp 60°-70° C. as the free base,and 180°-200° C. as the hydrochloride salt.

[0432]¹H-NMR (δ, CDCl₃): 2.05 (m, 2H), 2.87 (m, 1H), 3.05 (m, 1H), 3.14(m, 1H), 3.25 (m, 1H), 4.73 (bs, 2H), 4.94 (m, 1H), 6.37 (d, J=8, 1H),6.74 (d, J=8, 1H), 6.79 (d, J=7, 1H), 7.42 (m, 4H), 8.10 (m, 1H), 8.24(m, 1H).

[0433]¹³C-NMR (δ, CDCl₃): 33.44, 46.13, 53.62, 76.81, 105.43, 106.47,114.91, 122.06, 124.98, 125.70, 126.13, 126.54, 127.00, 131.35, 132.23,137.82, 153.29, 157.56, 158.23.

[0434] MS (%): 306 (parent+1, 100).

[0435] HRMS Calc'd. for C₁₉H₂₀N₃O: 306.1606. Found: 306.1608.

EXAMPLE 29

[0436]6-[4-(1-Isobutyl-piperidin4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0437] Prepared as in Example 24, in 38% yield, mp 198°-210° C., as thehydrochloride salt.

[0438]¹H-NMR (δ, CDCl₃): 0.92 (d, J=7, 6H), 1.81 (m, 1H), 2.01 (m, 2H),2.12 (m, 2H), 2.16 (d, J=7, 2H), 2.39 (m, 2H), 2.75 (m, 2H), 4.59 (m,3H), 6.46 (d, J=8, 1H), 6.87 (m, 2H), 7.4-7.6 (m, 4H), 8.09 (m, 1H),8.33 (m, 1H).

[0439]¹³C-NMR (δ, CDCl₃): 20.92, 25.59, 30.46, 50.83, 66.81, 72.56,106.06, 106.42, 115.16, 122.30, 124.92, 125.63, 126.49, 126.70, 127.07,131.24, 132.33, 137.89, 153.14, 157.76, 158.00.

[0440] MS (%): 376 (parent+1, 100).

[0441] Anal. Calc'd. for C₂₄H₂₉N₃O.2HCl.3/2H₂O: C 60.63, H 7.21, N 8.84.Found: C 60.77, H 7.30, N 8.48.

EXAMPLE 30

[0442]6-[4-(1-Furan-2-ylmethyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0443] Prepared as in Example 24, in 38% yield, mp 178°-195° C., as thehydrochloride salt.

[0444]¹H-NMR (δ, CDCl₃): 2.07 (m, 4H), 2.48 (m,. 2H), 2.76 (m, 2H), 3.59(s, 2H), 4.5 (bs, 2H), 4.62 (m, 1H), 6.21 (m, 1H), 6.31 (m, 1H), 6.45(d, J=8, 1H), 6.85 (m, 2H), 7.4-7.6 (m, 5H), 8.09 (m, 1H), 8.32 (m, 1H).

[0445]¹³C-NMR (δ, CDCl₃): 30.42, 49.93, 54.93, 72.00, 106.08, 106.44,108.69, 109.98, 115.16, 122.30, 124.95, 125.61, 126.49, 126.70, 127.05,131.29, 132.33, 137.89, 142.07, 151.74, 153.06, 157.73, 158.02.

[0446] MS (%): 400 (parent+1, 100).

[0447] Anal. Calc'd. for C₂₅H₂₅N₃O₂.2HCl.9/4H₂O: C 58.54, H 6.19, N8.19. Found: C 58.66, H6.13, N8.04.

EXAMPLE 31

[0448]6-[4-(1-Isobutyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0449] Prepared as in Example 24, in 45% yield, mp 78°-85° C., as thehydrochloride salt.

[0450]¹H-NMR (δ, CDCl₃): 0.94 (d, J=7, 6H), 1.76 (m, 1H), 2.14 (m, 1H),2.2-2.4 (m, 3H), 2.6-2.9 (m, 3H), 3.10 (m, 1H), 4.59 (bs, 2H), 5.03 (m,1H), 6.45 (d, J=8, 1H), 6.75 (d, J=8, 1H), 6.85 (d, J=8, 1H), 7.4-7.6(m, 4H), 8.10 (m, 1H), 8.33 (m, 1H).

[0451]¹³C-NMR (δ, CDCl₃): 20.35, 21.02, 27.31, 32.20, 53.31, 60.50,64.82, 105.29, 106.42, 115.15, 122.37, 124.92, 125.56, 126.16, 126.56,127.05, 131.20, 132.21, 137.88, 153.66, 157.73, 158.03.

[0452] MS (%): 362 (parent+1, 100).

[0453] HRMS Calc'd. for C₂₃H₂₈N₃O: 362.2232. Found: 362.2217.

EXAMPLE 32

[0454]6-[4-(1-Furan-2-ylmethyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0455] Prepared as in Example 24, in 46% yield, mp 140°-160° C., as thehydrochloride salt.

[0456]¹H-NMR (δ, CDCl₃): 2.15 (m, 1H), 2.38 (m, 1H), 2.7-2.9 (m, 3H),3.21 (m, 1H), 3.72 (AB_(q), J=7, Dn=20, 2H), 4.60 (bs, 2H), 5.03 (m,1H), 6.21 (m, 1H), 6.31 (m, 1H), 6.44 (d, J=8, 1H), 6.72 (d, J=8, 1H),6.84 (d, J=7, 1H), 7.37 (m, 1H), 7.44 (m, 4H), 8.10M, 1H), 8.32 (m, 1H).

[0457]¹³C-NMR (δ, CDCl₃): 32.34, 51.72, 52.53, 59.80, 76.70, 105.19,106.47, 107.98, 110.03, 115.12, 122.37, 124.95, 125.57, 126.06, 126.59,127.02, 131.30, 132.21, 137.89, 141.98, 152.21, 153.53, 157.67, 158.05.

[0458] MS (%): 386 (parent+1, 100).

[0459] Anal. Calc'd. for C₂₄H₂₃N₃O₂.2HCl.9/4H₂O: C 57.78, H 5.96, N8.42. Found: C 57.96, H 5.98, N 8.14.

EXAMPLE 33

[0460]6-[4-(1-Methyl-piperidin-4-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0461] Prepared as in Example 24, in 90% yield, mp 179°-187° C., as thehydrochloride salt.

[0462]¹H-NMR (δ, CDCl₃): 2.00 (m, 4H), 2.26 (s, 3H), 2.33 (m, 2H), 2.645(m, 2H), 4.54 (m, 1H), 4.76 (bs, 2H), 6.35 (d, J=8, 1H), 6.78 (d, J=7,1H), 6.81 (d, J=8, 1H), 7.41 (m, 4H), 8.09 (m, 1H), 8.33 (m, 1H).

[0463]¹³C-NMR (δ, CDCl₃): 30.46, 46.13, 52.35, 71.64, 105.93, 106.51,114.88, 122.27, 124.95, 125.66, 126.47, 126.59, 127.07, 131.26, 132.32,137.84, 153.02, 157.47, 158.26.

[0464] MS (%): 334 (parent+1, 100).

[0465] Anal. Calc'd. for C₂₁H₂₃N₃O.2HCl.H₂O0(C₄H₈O): C 60.48, H 7.11, N8.46. Found: C 60.19, H 7.61, N 9.94.

EXAMPLE 34

[0466]6-[4-(1-Methyl-pyrrolidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0467] Prepared as in Example 24, in 77% yield, mp 138°-145° C., as thehydrochloride salt.

[0468]¹H-NMR (δ, CDCl₃): 2.10 (m, 1H), 2.35 (m, 1H), 2.395 (s, 3H), 2.55(m, 1H), 2.79 (m, 1H), 2.89 (m, 1H), 2.99 (m, 1H), 4.69 (bs, 2H), 5.01(m, 1H), 6.41 (d, J=8, 1H), 6.70 (d, J=8, 1H), 6.81 (d, J=8, 1H), 7.43(m, 4H), 8.07 (m, 1H), 8.32 (m, 1H).

[0469]¹³C-NMR (δ, CDCl₃): 32.97, 42.10, 55.09, 62.34, 77.39, 105.13,106.51, 115.04, 122.39, 124.94, 125.54, 126.03, 126.57, 126.99, 131.26,132.21, 137.88, 153.53, 157.57, 158.15.

[0470] MS (%): 320 (parent+1, 100).

[0471] Anal. Calc'd. for C₂₀H₂₁N₃O.2HCl.3H₂O: C 53.82, H 6.55, N 9.41.Found: C 54.02, H 6.45, N 9.13.

EXAMPLE 35

[0472] 6-[4-(3-Dimethylamino-propoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0473] Prepared as in Example 24, in 91.5% yield, mp 105°-120° C., asthe hydrochloride salt.

[0474]¹H-NMR (δ, CDCl₃): 2.08 (m, 2H), 2.26 (s, 6H), 2.54 (t, J=7, 2H),4.18 (t, J=6, 2H), 4.72 (bs, 2H), 6.40 (d, J=8, 1H), 6.81 (m, 2H), 7.45(m, 4H), 8.08 (m, 1H), 8.32 (m, 1H).

[0475]¹³C-NMR (δ, CDCl₃): 27.47, 45.41, 56.52, 66.39, 104.16, 106.47,115.01, 122.03, 124.91, 125.63, 125.77, 126.47, 127.20, 131.17, 132.08,137.85, 154.78, 157.63, 158.17.

[0476] MS (%): 322 (parent+1, 100).

[0477] Anal. Calc'd. for C₂₀H₂₃N₃O.2HCl.7/2H₂O: C 52.52, H 7.05, N 9.19.Found: C 52.62, H 6.77, N 8.73.

EXAMPLE 36

[0478]6-[4-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0479] Prepared as in Example 24, in 89% yield, mp 220°-228° C., as thehydrochloride salt.

[0480]¹H-NMR (δ, CDCl₃): 1.41 (m, 1H), 1.54 (m, 1H), 1.71 (m, 1H), 2.09(m, 1H), 2.27 (m, 1H), 2.78 (m, 3H), 2.96 (m, 2H), 3.30 (m, 1H), 4.56(m, 1H), 4.71 (bs, 2H), 6.39 (d, J=8, 1H), 6.70 (d, J=8, 1H), 6.81 (d,J=7, 1H), 7.43 (m, 4H), 8.09 (m, 1H), 8.32 (m, 1H).

[0481]¹³C-NMR (δ, CDCl₃): 19.61, 24.37, 25.15, 46.53, 47.33, 55.73,73.44, 105.38, 106.47, 114.95, 122.07, 125.01, 125.73, 126.24, 126.54,127.05, 131.29, 132.33, 137.84, 153.00, 157.56, 158.20.

[0482] MS (%): 346 (parent+1, 100).

[0483] Anal. Calc'd. for C₂₂H₂₃N₃O.2HCl5/2H₂O: C 57.02, H 6.52, N 9.07.Found: C 57.07, H 6.27, N 8.88.

EXAMPLE 37

[0484]6-[4-(2-Dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0485] A. 4-Bromo-5,6,7,8-tetrahydro-1-benzyloxynaphthalene

[0486] To a 250 mL round-bottomed flask equipped with addition funneland N₂ inlet were added 2.96 g (20 mmol)5,6,7,8-tetrahydro-naphthalen-1-ol and 50 mL 1,2-dichloroethane, andwith stirring a solution of 9.64 g (20 mmol) tributylammonium tribromidein 30 mL 1,2- dichloroethane dropwise over 10 min. After stirring anadditional 10 min at room temperature, the solution was washed withwater, dilute aqueous sodium bisulfite, and water, dried over sodiumsulfate, and evaporated. The mixture of product and tributylammoniumbromide was used directly.

[0487]¹H-NMR (δ, CDCl₃): 1.70 (m, 4H), 2.56 (t, J=6, 2H), 2.61 (t, J=6,2H), 7.02 (AB, 2H), 8.0 (bs, 1H, OH).

[0488]¹³C-NMR (δ, CDCl₃): 22.2, 22.9, 23.8, 30.5, 114.0, 114.7, 126.6,129.0, 136.7, 154.1.

[0489] The above oil was dissolved in 100 mL acetonitrile, and treatedwith 3.57 mL (30 mmol) benzyl bromide and 5.53 g (40 mmol) potassiumcarbonate, the refluxed 14 h. TLC showed a major spot at R_(f)=0.3 in10% methylene chloride/hexane (with benzyl bromide at R_(f)=0.4). Thereaction was cooled, poured into dilute aqueous hydrochloric acid/ethylacetate, and the organic layer separated, washed with water and brine,dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel using methylene chloride/hexane as eluantto afford 4.0 g (63%) of an oil. 1H-NMR (δ, CDCl₃): 1.77 (m, 4H), 2.75(m, 4H), 5.045 (s, 2H), 6.62 (d, J=9, 1H), 7.3-7.5 (m, 6H).

[0490]¹³C-NMR (δ, CDCl₃): 22.2, 22.9, 24.0, 30.7, 69.9, 109.8, 116.7,127.1, 127.9, 128.6, 129.1, 129.3, 137.2, 137.5, 155.6.

[0491] B. 5,6,7,8-tetrahydro-1-benzyloxynaphthalene4-boronic Acid

[0492] Prepared as in Example 12B as a white solid after triturationwith hexane, mp 199°-205° C., in 72% yield.

[0493]¹H-NMR (δ, CDCl₃): 1.72 (m, 4H), 2.70 (m, 4H), 5.005 (s, 2H), 6.66(m, 1H), 7.01 (d, J=8, 1H), 7.2-7.4 (m, 5H).

[0494]¹³C-NMR (δ, CDCl₃): 22.6, 22.9, 23.4, 30.0, 107.8, 125.9, 127.0,127.6, 128.4, 131.1, 137.5, 140.8, 156.9.

[0495] C.2-(2,5-Dimethylpyrrolyl)-6-[4-benzyloxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0496] Prepared as in Example 12C in 100% yield as an oil.

[0497]¹H-NMR (δ, CDCl₃): 1.81 (m, 2H), 1.91 (m, 2H), 2.29 (s, 6H), 2.93(m, 4H), 5.19 (s, 2h), 6.02 (s, 2H), 6.91 (d, J=8, 1H), 7.21 (d, J=8,1H), 7.32 (d, J=8, 1H), 7.4-7.6 (m, 6H), 7.89 (t, J=8, 1H). ¹³C-NMR (δ,CDCl₃): 13.5, 22.5, 23.0, 24.0, 28.9, 69.8, 106.8, 108.2, 119.6, 123.1,126.8, 127.2, 127.8, 12.9, 128.6, 128.7, 132.8, 136.8, 137.6, 138.0,151.4, 156.8, 160.4.

[0498] MS (%): 409 (parent+1, 100).

[0499] D.2-(2,5-Dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0500] Prepared as in Example 12D in 100% yield as an low melting solid.

[0501]¹H-NMR (δ, CDCl₃): 1.67 (m, 2H), 1.77 (m, 2H), 2.16 (s, 6H), 2.63(m, 2H), 2.73 (m, 2H), 5.89 (s, 2H), 6.3 (bs, 1H, OH), 6.51 (d, J=8,1H), 7.02 (d, J=8, 1H), 7.13 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.83 (t,J=8, 1H).

[0502]¹³C-NMR (δ, CDCl₃): 13.3, 22.3, 22.8 23.3, 28.6, 106.6, 112.1,119.7, 123.3, 124.2, 127.8, 128.7, 131.9, 136.6, 138.1, 151.2, 154.4,160.5.

[0503] MS (%): 319 (parent+1, 100).

[0504] E.2-(2,5-Dimethylpyrrolyl)-6-[4-carboethoxymethoxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0505] Prepared as in Example 12E in 83.5% yield as an oil.

[0506]¹H-NMR (δ, CDCl₃): 1.31 (t, J=7, 3H), 1.71 (m, 2H), 1.83 (m, 2H),2.19 (s, 6H), 4.26 (q, J=7, 2H), 4.66 (s, 2H), 5.90 (s, 2H), 6.64 (d,J=8, 1H), 7.12 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.82(t, J=8, 1H).

[0507]¹³C-NMR (δ, CDCl₃): 13.4, 14.2, 22.3, 22.9, 23.7, 28.7, 61.2,65.5, 106.7, 107.8, 119.6, 123.0, 126.9, 127.7, 128.5, 133.4, 137.0,138.1, 151.3, 156.0, 160.1, 169.0.

[0508] MS (%): 405 (parent+1, 100).

[0509] F.2-(2,5-Dimethylpyrrolyl)-6-[4-carboxymethoxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0510] Prepared as in Example 12F in 100% yield as a solid, mp 199°-206°C.

[0511]¹H-NMR (δ, CDCl₃): 1.62 (m, 2H), 1.72 (m, 2H), 2.08 (s, 6H), 2.66(m, 2H), 2.75 (m, 2H), 4.56 (s, 2H), 5.81 (s, 2H), 6.58 (d, J=8, 1H),7.09 (m, 2H), 7.31 (d, J=8, 1H), 7.80 (t, J=8, 1H).

[0512]¹³C-NMR (δ, CDCl₃): 12.95, 22.1, 22.6, 23.4, 28.4, 65.0, 106.5,107.7, 119.9, 123.3, 126.7, 127.4, 128.5, 132.8, 136.6, 138.3, 151.1,155.9, 160.1, 171.2.

[0513] MS (%): 377 (parent+1, 100).

[0514] G.2-(2,5-Dimethylpyrrolyl)-6-[4-(N,N-dimethylcarboxamido)methoxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0515] Prepared as in Example 12G in 100% yield as an oil.

[0516]¹H-NMR (δ, CDCl₃): 1.67 (m, 2H), 1.77 (m, 2H), 2.14 (s, 6H), 2.76(m, 4H), 2.96 (s, 3H), 3.08 (s, 3H), 4.71 (s, 2H), 5.86 (s, 2H), 6.75(d, J=8, 1H), 7.11 (d, J=8, 1H), 7.16 (d, J=8, 1H), 7.34 (d, J=8, 1H),7.82 (t, J=8, 1H).

[0517]¹³C-NMR (δ, CDCl₃): 13.3, 22.2, 22.8, 23.6, 28.6, 35.7, 36.7,67.7, 106.5, 107.7, 119.6, 122.9, 126.5, 127.8, 128.6, 133.2, 136.8,138.0, 151.2, 155.9, 160.2, 168.1.

[0518] MS (%): 404 (parent+1, 100).

[0519] H.2-(2,5-Dimethylpyrrolyl)6-[4-(N,N-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0520] Prepared as in Example 12H in 93% yield as an oil.

[0521]¹H-NMR (δ, CDCl₃): 1.69 (m, 2H), 1.78 (m, 2H), 2.16 (s, 6H), 2.36(s, 6H), 2.73 (t, J=7, 2H), 2.78 (m, 4H), 4.11 (t, J=7, 2H), 5.88 (s,2H), 6.74 (d, J=8, 1H), 7.11 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.36 (d,J=8, 1H), 7.81 (t, J=8, 1H).

[0522]¹³C-NMR (δ, CDCl₃): 13.3, 22.3, 22.9, 23.7, 28.7, 46.2, 58.4,66.6, 106.6, 107.6, 119.5, 122.95, 126.5, 127.7, 128.6, 132.4, 136.6,137.9, 151.2, 156.9, 160.35.

[0523] MS (%): 390 (parent+1, 100).

[0524] I.6-[4-N,N-Dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0525] Prepared as in Example 12I in 57% yield as the hydrochloridesalt, mp 239°-242° C. from methanol/isopropyl ether.

[0526]¹H-NMR (δ, CDCl₃): 1.64 (m, 2H), 1.71 (m, 2H), 2.33 (s, 6H), 2.67(m, 4H), 2.74 (t, J=6, 2H), 4.07 (t, J=6, 2H), 4.55 (bs, 2H), 6.36 (d,J=8, 1H), 6.62 (d, J=8, 1H), 6.67 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.40(t, J=8, 1H).

[0527]¹³C-NMR (δ, CDCl₃): 22.3, 22.8 23.6, 28.1, 46.0, 58.2, 66.4,106.0, 107.4, 114.3, 126.2, 126.8, 133.5, 136.2, 137.6, 156.3, 157.6,158.8.

[0528] MS (%): 312 (parent+1, 100).

[0529] Anal. Calc'd. for C₁₉H₂₅N₃O.2HCl.1/4H₂O: C 58.69, H 7.13, N10.81. Found: C 58.72, H 7.14, N 10.79.

[0530]6-[4-(N,N-Dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylaminemay also be prepared by the following method:

[0531] J.4-Bromo-1-(N,N-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalene

[0532] To a 1 L round-bottomed flask equipped with condenser and N₂inlet were added 10.0 g (44 mmol)4-bromo-5,6,7,8-tetrahydro-naphthalen-1-ol (Example 37A), 19 g (130mmol) 2-dimethylaminoethyl chloride hydrochloride, 30.3 g (220 mmol)powdered potassium carbonate, and 600 mL acetonitrile. The reaction wasrefluxed 60 hours, followed by an additional portion of the chloride andcontinued refluxing for 24 hours. The reaction was cooled, filtered andconcentrated. The residue was chromatographed on silica gel usingmethanol/methylene chloride as eluant to afford 8.55 g (65%) of a lightbrown oil.

[0533]¹H-NMR (δ, CDCl₃): 1.72 (m, 4H), 2.33 (s, 6H), 2.63 (m, 2H), 2.68(m, 2H), 2.73 (t, J=6, 2H), 4.01 (t, J=6, 2H), 6.53 (d, J=8, 1H), 7.28(d, J=8, 1H).

[0534]¹³C-NMR (δ, CDCl₃): 22.1, 22.8, 23.7, 30.5, 46.0, 538.2, 66.6,109.2, 116.4, 128.8, 129.2, 137.2, 155.6.

[0535] MS: 298/300 (parent+1).

[0536] K.1-(N,N-Dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalene-4-boronicAcid

[0537] To a 1 L 3N round-bottomed flask equipped with septum and N₂inlet were added 8.55 g (28.7 mmol)4-bromo-1-(2-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalene and 300mL dry tetrahydrofuran. The solution was cooled to −70° C., and 13.8 mL(34.4 mmol) of a 2.5M solution of butyl lithium in hexanes was added.The reaction was stirred at −70° C. for 1 h, then 5.9 mL (34.4 mmol)triethyl borate was added, and the reaction stirred at −70° C. for 2 hand warmed to room temperature overnight The reaction was quenched withaqueous saturated ammonium chloride solution and extracted three timeswith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated. The residue was triturated with hexaneto a white solid, 6.3 g (83.5%).

[0538]¹H-NMR (δ, CDCl₃): 1.79 (m, 4H), 2.44 (s, 6H), 2.68 (m, 2H), 2.89(m, 2H), 3.32 (m, 2H), 4.19 (m, 2H), 6.74 (d, J=8, 1H), 8.03 (d, J=8,1H).

[0539] L.2-(2,5-Dimethylpyrrolyl)-6-[4-(N,N-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0540] To a 500 mL round-bottomed flask equipped with condenser and N₂inlet were added 6.3 g (23.4 mmol)1-(N,N-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalene-4-boronicacid, 6.0 g (23.4 mmol) 6-bromo-2-(2,5-dimethylpyrrolyl)pyridine, 10.1 g(95.6 mmol) sodium carbonate, 552 mg tetrakistriphenylphosphinepalladium, 200 mL ethanol and 20 mL water. The reaction was refluxed for20 hours, cooled, and filtered. The filtrate was concentrated, taken upin 1N sodium hydroxide solution, and extracted three times into ethylacetate. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine, dried over sodium sulfate, andevaporated. The residue was chromatographed on silica gel usingmethanol/methylene chloride as eluant to afford 7.67 g (82%) of theproduct as an oil.

[0541]¹H-NMR (δ, CDCl₃): 1.69 (m, 2H), 1.78 (m, 2H), 2.16 (s, 6H), 2.36(s, 6H), 2.73 (t, J=7, 2H), 2.78 (m, 4H), 4.11 (t, J=7, 2H), 5.88 (s,2H), 6.74 (d, J=8, 1H), 7.11 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.36 (d,J=8, 1H), 7.81 (t, J=8, 1H).

[0542]¹³C-NMR (δ, CDCl₃): 13.3, 22.3, 22.9, 23.7, 28.7, 46.2, 58.4,66.6, 106.6, 107.6, 119.5, 122.95, 126.5, 127.7, 128.6, 132.4, 136.6,137.9, 151.2, 156.9, 160.35.

[0543] MS (%): 390 (parent+1, 100).

[0544] This material was then converted to6-[4-(N,N-dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine by the method given inExample 37I in 83% yield.

EXAMPLE 38

[0545]6-[4-(2-Pyrrolidin-1-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0546] Prepared as in Example 37, in 58% yield, as a hygroscopic solidas the hydrochloride salt.

[0547]¹H-NMR (δ, CDCl₃): 1.64 (m, 2H), 1.74 (m, 2H), 1.77 (m, 4H), 2.62(m, 4H), 2.68 (m, 4H), 2.89 (t, J=6, 2H), 4.10 (t, J=6, 2H), 4.52 (bs,2H), 6.37 (d, J=8, 1H), 6.63 (d, J=8, 1H), 6.65 (d, J=8, 1H), 7.07 (d,J=8, 1H), 7.40 (t J=8, 1H).

[0548]¹³C-NMR (δ, CDCl₃): 22.4, 22.9, 23.5, 23.7, 28.2, 54.9, 55.0,67.4, 106.1, 107.5, 114.4, 126.3, 126.9, 133.5, 136.3, 137.7, 156.4,157.7, 158.9.

[0549] MS (%): 338 (parent+1, 100).

[0550] Anal. Calc'd. for C₂₁H₂₇N₃O.2HCl.3H₂O: C 54.31, H 7.60, N 9.05.Found: C 54.00, H 7.83, N 9.19.

EXAMPLE 39

[0551]6-{4-[2-(tert-Butyl-methyl-amino)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine

[0552] Prepared as in Example 37, in 93% yield, mp 65°-90° C., as thehydrochloride salt.

[0553]¹H-NMR (δ, CDCl₃): 1.08 (s, 9H), 1.64 (m, 2H), 1.74 (m, 2H), 2.325(s, 3H), 2.68 (m, 4H), 2.79 (t, J=6, 2H), 4.01 (t, J=6, 2H), 4.50 (bs,2H), 6.37 (d, J=8, 1H), 6.64 (d, J=8, 1H), 6.68 (d, J=8, 1H), 7.08 (d,J=8, 1H), 7.41 (t, J=8, 1H).

[0554]¹³C-NMR (δ, CDCl₃): 22.44, 22.89, 23.72, 26.07, 28.24, 36.67,50.50, 67.89, 106.05, 107.50, 114.52, 126.21, 126.88, 133.32, 136.19,137.73, 156.56, 157.65, 158.97.

[0555] MS (%): 354 (parent+1, 100).

[0556] Anal. Calc'd. for C₂₂H₃₁N₃O.2HCl.3H₂O: C 55.00, H 8.18, N 8.75.Found: C 55.29, H 8.25, N 8.57.

EXAMPLE 40

[0557]6-[4-(2-Diisopropylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0558] Prepared as in Example 37, in 83% yield, mp 50°-60° C., as thehydrochloride salt.

[0559]¹H-NMR (δ, CDCl₃): 1.04 (d, J=7, 6H), 1.65 (m, 2H), 1.75 (m, 2H),2.69 (m, 4H), 2.83 (t, J=7, 2H), 3.05 (septet, J=7, 1H), 3.90 (t, J=7,2H), 4.55 (bs, 2H), 6.38 (d, J=8, 1H), 6.65 (d, J=8, 1H), 6.70 (d, J=8,1H), 7.09 (d, J=8, 1H), 7.42 (t, J=8, 1H).

[0560]¹³C-NMR (δ, CDCl₃): 20.79, 22.37, 22.81, 23.63, 28.16, 44.51,49.42, 69.26, 105.99, 107.53, 114.39, 126.14, 126.79, 133.18, 136.12,137.67, 156.51, 157.60, 158.88.

[0561] MS (%): 368 (parent+1, 100).

[0562] Anal. Calc'd. for C₂₃H₃₃N₃O.2HCl.5/2H₂O.(C₄H₁₀O): C 57.95, H9.01, N 7.51. Found: C 57.74, H 8.62, N 7.25.

EXAMPLE 41

[0563]6-[4-(2-Diethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0564] Prepared as in Example 37, in 42% yield, as a hygroscopic solidas the hydrochloride salt.

[0565]¹H-NMR (δ, CDCl₃): 1.07 (t, J=7, 6H), 1.66 (m, 2H), 1.735 (m, 2H),2.6-2.8 (m, 8H), 2.91 (t, J=6, 2H), 4.05 (t, J=6, 2H), 4.49 (bs, 2H),6.39 (d, J=8, 1H), 6.65 (d, J=8, 1H), 6.69 (d, J=8, 1H), 7.09 (d, J=8,1H), 7.43 (t, J=8, 1H).

[0566]¹³C-NMR (δ, CDCl₃): 11.92, 22.35, 22.80, 23.60, 25.28, 28.11,47.78, 51.67, 66.62, 105.96, 107.43, 114.43, 126.20, 126.77, 133.39,136.20, 137.64, 156.43, 157.54, 158.91.

[0567] MS (%): 340 (parent+1, 100).

EXAMPLE 42

[0568]6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine

[0569] Prepared as in Example 37, in 67% yield, as an amorphous solid,as the hydrochloride salt.

[0570]¹H-NMR (δ, CDCl₃): 1.67 (m, 2H), 1.79 (m, 2H), 2.73 (m, 4H), 2.94(m, 4H), 3.03 (t, J=6, 2H), 3.83 (s, 2H), 4.24 (t, J=6, 2H), 4.87 (bs,2H), 6.37 (d, J=8, 1H), 6.65 (d, J=8, 1H), 6.74 (d, J=8, 1H), 7.0-7.2(m, 5H), 7.43 (t, J=8, 1H).

[0571]¹³C-NMR (δ, CDCl₃): 22.39, 22.81, 23.73, 28.17, 28.82, 32.46,51.37, 56.38, 56.86, 66.47, 106.29, 107.47, 114.25, 125.56, 126.10,126.14, 126.53, 126.95, 128.61, 133.25, 133.98, 134.47, 136.30, 137.84,156.31, 157.79, 158.46.

[0572] MS (%): 400 (parent+1, 100).

[0573] HRMS Calc'd. for C₂₆H₃N₃O: 400.2383. Found: 400.2389.

EXAMPLE 43

[0574]6-[4-(2-Piperidin-1-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0575] Prepared as in Example 37, in 93% yield, as a foam, as thehydrochloride salt.

[0576]¹H-NMR (δ, CDCl₃): 1.42 (m, 2H), 1.58 (m, 6H), 1.74 (m, 2H), 2.51(m, 4H), 2.67 (m, 4H), 2.79 (t, J=6, 2H), 4.10 (t, J=6, 2H), 4.535 (bs,2H), 6.34 (d, J=8, 1H), 6.63 (d, J=8, 1H), 6.67 (d, J=8, 1H), 7.08 (d,J=8, 1H), 7.39 (t, J=8, 1H).

[0577]¹³C-NMR (δ, CDCl₃): 22.43, 22.87, 23.71, 24.18, 26.04, 28.23,55.04, 58.01, 66.24, 106.05, 107.56, 114.37, 126.26, 126.88, 133.55,136.26, 137.70, 156.38, 157.72, 158.90.

[0578] MS (%): 352 (parent+1, 100).

[0579] Anal. Calc'd. for C₂₂H₂₃N₃O.2HCl.2H₂O1/2(C₄H₁₀O): C 57.94, H8.10, N 8.45. Found: C 58.25, H 7.78, N 8.69.

EXAMPLE 44

[0580]6-[4-(2-Morpholin-4-yl-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0581] Prepared as in Example 37, in 67% yield, as a white amorphoussolid.

[0582]¹H-NMR (d, CDCl₃): 1.64 (m, 2H), 1.74 (m, 2H), 2.58 (m, 4H), 2.68(m, 4H), 2.81 (t, J=6, 2H), 3.71 (m, 4H), 4.11 (t, J=6, 2H), 4.45 (bs,2H), 6.39 (d, J=8, 1H), 6.66 (m, 2H), 7.09 (d, J=8, 1H), 7.43 (t, J=8,1H).

[0583]¹³C-NMR (d, CDCl₃): 22.39, 22.85, 23.72, 28.21, 54.16, 57.73,66.26, 67.03, 106.12, 107.61, 114.53, 126.36, 126.88, 136.39, 137.80,156.30, 157.57, 158.83.

[0584] MS (%): 354 (parent+1, 100).

[0585] Anal. Calc'd. for C₂₁H₂₇N₃O₂.1/2H₂O: C 69.59, H 7.79, N 11.59.Found: C 69.61, H 7.51, N 11.56.

EXAMPLE 45

[0586]6-{4-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin6-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine

[0587] Prepared as in Example 37, in 82% yield, as a white, amorphoussolid, as the hydrochloride salt.

[0588]¹H-NMR (d, CDCl₃): 1.65 (m, 2H), 1.76 (m, 2H), 2.72 (m, 4H), 2.84(m, 4H), 2.98 (t, J=6, 2H), 3.69 (s, 2H), 4.20 (t, J=6, 2H), 4.52 (bs,2H), 5.86 (s, 2H), 6.37 (d, J=8, 1H), 6.47 (s, 1H), 6.55 (s, 1H), 6.65(d, J=8, 1H), 6.68 (d, J=8, 1H), 7.11 (d, J=8, 1H), 7.42 (t, J=8, 1H).

[0589]¹³C-NMR (d, CDCl₃): 22.44, 22.89, 23.79, 28.25, 29.09, 51.47,56.57, 56.87, 66.69, 100.59, 106.11, 106.47, 107.57, 108.43, 114.46,126.31, 126.92, 127.04, 127.51, 133.65, 136.38, 137.76, 145.67, 146.03,156.35, 157.68, 158.87.

[0590] MS (%): 444 (parent+1, 100).

[0591] Anal. Calc'd. for C₂₇H₂₉N₃O₃: C 73.11, H 6.59, N 9.47. Found: C73.37, H 7.19, N 8.96.

[0592] HRMS Calc'd. for C₂₇H₃₀N₃O₃: 444.2287. Found: 444.2287.

EXAMPLE 46

[0593]6-{4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine

[0594] Prepared as in Example 37, in 100% yield, as an amorphous solid,as the hydrochloride salt.

[0595]¹H-NMR (d, CDCl₃): 1.62 (m, 2H), 1.72 (m, 2H), 2.26 (s, 3H),2.4-2.8 (m, 12H), 2.81 (t, J=6, 2H), 4.09 (t, J=6, 2H), 4.50 (bs, 2H),6.35 (d, J=8, 1H), 6.63 (m, 2H), 7.07 (d, J=8, 1H), 7.39 (t, J=8, 1H).

[0596]¹³C-NMR (d, CDCl₃): 22.4, 22.9, 23.37, 28.2, 46,1, 53.37, 55.2,57.3, 66.3, 106.1, 107.6, 114.4, 126.3, 126.9, 133.6, 136.3, 137.7,156.3, 157.7, 158.9.

[0597] MS (%): 367 (parent+1, 100).

[0598] Anal. Calc'd. for C₂₂H₃₀N₄O.3HCl.H₂O.1/2(C₄H₁₀O): C 54.29, H7.59, N 10.55. Found: C 54.20, H 7.59, N 10.50.

EXAMPLE 47

[0599]6-{4-[2-(4-Dimethylamino-piperidin-1-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-pyridin-2-ylamine

[0600] Prepared as in Example 37, in 92% yield, as an amorphous solid,as the hydrochloride salt.

[0601]¹H-NMR (d, CDCl₃): 1.54 (m, 2H), 1.64 (m, 2H), 1.77 (m, 4H), 2.12(m, 3H), 2.26 (s, 6H), 2.66 (m, 4H), 2.80 (t, J=6, 2H), 3.03 (m, 2H),4.09 (t, J=6, 2H), 4.48 (bs, 2H), 6.37 (d, J=8, 1H), 6.64 (d, J=8, 1H),6.67 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.41 (t, J=8, 1H).

[0602]¹³C-NMR (d, CDCl₃): 22.32, 22.78, 23.61, 28.27, 41.56, 53.55,57.15, 62.04, 66.31, 105.96, 107.51, 114.36, 126.23, 126.79, 133.52,136.22, 137.62, 149.63, 156.25, 157.56, 158.85.

[0603] MS (%): 395 (parent+1, 100).

[0604] HRMS Calc'd. for C₂₄H₃₅N₄O: C 395.2807. Found: 395.2811.

EXAMPLE 48

[0605]6-[4-(Piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0606] A.2-(2,5-Dimethylpyrrolyl)-6-[4-N-toluenesulfonyl)-(piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine

[0607] To a 125 mL round-bottomed flask equipped with condenser and N₂inlet were added 2.0 g (6.3 mmol)2-2,5-dimethylpyrrolyl)-6-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-pyridine,4.0 g (9.4 mmol) 3-(hydroxymethyl)-piperidine-di-p-toluenesulfonate, 3.5g (25.2 mol) potassium carbonate, and 60 mL dry dimethylformamide. Thereaction was heated at 140° C. for 14 hours, cooled, and poured intowater. The mixture was extracted with ethyl acetate, and the organiclayer washed thoroughly with water and brine, dried over sodium sulfate,and evaporated. The residue was chromatographed on silica gel usinghexane/ethyl acetate as eluant to afford 3.1 g (86%) of a white solid.

[0608]¹H-NMR (δ, CDCl₃): 1.25 (m, 2H), 1.67 (m, 4H), 1.77 (m, 4H), 2.15(s, 6H), 2.42 (s, 3H), 2.66 (m, 2H), 2.76 (m, 2H), 3.6-3.9 (m, 5H), 5.87(s, 2H), 6.66 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.18 (d, J=8, 1H),7.3-7.4 (m, 3H), 7.63 (m, 2H), 7.82 (t, J=8, 1H).

[0609]¹³C-NMR (δ, CDCl₃): 21.43, 22.19, 22.74, 23.53, 23.97, 26.44,28.53, 35.74, 46.60, 49.30, 69.59, 106.48, 107.31, 119.42, 122,83,126.39, 127.63, 128.55, 129.51, 132.52, 133.17, 136.62, 137.77, 143.34,151.14, 156.50, 160.11.

[0610] MS (%): 570 (parent+1, 100).

[0611] B.6-[4-N-(4-toluenesulfonyl)-(piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0612] To a 500 mL round-bottomed flask equipped with condenser and N₂inlet were added 3.1 g (5.4 mmol)2-(2,5-dimethylpyrrolyl)-6-[4-N-(4-toluenesulfonyl)-piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine, 7.6 g (109 mmol)hydroxylamine hydrochloride, 250 mL ethanol, and 25 mL water. Thereaction was refluxed 5 days, cooled, and evaporated. The residue wastaken up in ethyl acetate and 1N hydrochloric acid, and the organiclayer washed with additional ethyl acetate and adjusted to pH 12 with 6Nsodium hydroxide solution, then extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, andevaporated to afford 2.87 g (100%) of a light brown foam.

[0613]¹H-NMR (δ, CDCl₃): 1.16 (m, 1H), 1.6-1.8 (m, 7H), 2.2-2.4 (m, 3H),2.41 (s, 3H), 2.7 (m, 4H), 3.7-3.9 (m, 4H), 4.51 (bs, 2H), 6.395 (d,J=8, 1H), 6.61 (d, J=8, 1H), 6.64 (d, J=8, 1H), 7.08 (d, J=8, 1H), 7.29(m, 2H), 7.42 (t, J=8, 1H), 7.62 (m, 2H).

[0614]¹³C-NMR (δ, CDCl₃): 21.53, 22.39, 22.85, 23.62, 24.09, 26.52,28.23, 35.84, 46.70, 49.43, 69.70, 106.19, 107.36, 114.43, 126.35,126.87, 127.73, 129.61, 133.16, 133.71, 136.44, 137.80, 143.42, 156.18,157.67, 158.73.

[0615] MS (%): 492 (parent+1, 100).

[0616] C.6-[4-Piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0617] To a three-necked round-bottomed flask equipped with condenser,septum and N₂ inlet were added 4.5 g (33.6 mmol) aluminum chloride and150 mL dry 1,2-dimethoxyethane. The reaction was cooled to 0° C., and 79mL (79 mmol) of a 1.0M solution of lithium aluminum hydride intetrahydrofuran was added. The reaction was stirred at room temperaturefor 30 min, then cooled to −70° C., and a solution of 2.77 g (5.6 mmol)6-[4-N-(4-toluenesulfonyl)-(piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylaminein 150 mL dry 1,2-dimethoxyethane was added over 10 min. The reactionwas stirred and warmed to room temperature, then heated at reflux for 3days. The reaction was cooled, quenched carefully with 1N hydrochloricacid, then adjusted to pH 12 with 6N sodium hydroxide solution. Themixture was extracted with several portions of methylene chloride, andthe organic layer washed with aqueous sodium bicarbonate solution andbrine, dried over sodium sulfate, and evaporated. The residue waschromatographed using methanol/methylene chloride/triethylamine aseluant to afford 784 mg (41.5%) of an off-white solid, which wasconverted to the hydrochloride salt.

[0618]¹H-NMR (δ, CDCl₃): 1.21 (m, 1H), 1.46 (m, 1H), 1.6-2.0 (m, 8H),2.4-2.6 (m, 2H), 2.66 (m, 3H), 3.1 (m, 2H), 3.76 (m, 2H), 4.57 (bs, 2H),6.35 (d, J=8, 1H), 6.60 (d, J=8, 1H), 6.63 (d, J=8, 1H), 7.39 (t, J=8,1H).

[0619]¹³C-NMR (δ, CDCl₃): 22.4, 22.9, 23.6, 25.3, 27.6, 28.2, 36.6,46.2, 49.3, 70.7, 106.2, 107.3, 114.4, 126.4, 126.8, 133.5, 135.3,137.8, 156.5, 157.8, 158.7.

[0620] MS (%): 338 (parent+1, 100).

[0621] Anal. Calc'd. for C₂₁H₂₇N₃.1/2H₂O: C 72.80, H 8.15, N 12.13.Found: C 73.11, H 8.29, N 11.89.

EXAMPLE 49

[0622]6-[4-(1-Methyl-piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0623] Prepared from Example 48 by reductive amination with formaldehydein formic acid, in 84.5% yield, as a yellow amorphous solid, as thehydrochloride salt.

[0624]¹H-NMR (δ, CDCl₃): 1.12 (m, 2H), 1.6-2.0 (m, 8H), 2.18 (m, 1H),2.29 (s, 3H), 2.69 (m, 4H), 2.79 (m, 1H), 3.00 (m, 1H), 3.81 (m, 2H),4.44 (bs, 2H), 6.40 (d, J=8, 1H), 6.65 (m, 2H), 7.08 (d, J=8, 1H), 7.43(t, J=8, 1H).

[0625]¹³C-NMR (δ, CDCl₃): 22.32, 22.80, 23.54, 24.83, 26.71, 28.16,36.45, 46.60, 56.13, 59.30, 70.68, 105.98, 107.24, 114.49, 126.26,126.74, 127.83, 133.29, 136.16, 137.68, 156.44, 157.49, 158.89.

[0626] MS (%): 352 (parent+1, 100).

[0627] HRMS Calc'd. for C₂₂H₃₀N₃O: 352.2389. Found: 352.2365.

EXAMPLE 50

[0628]6-[4-(1-Isobutyl-piperidin-3-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0629] Prepared from Example 48 by reductive amination withisobutyraldehyde, in 5.7% yield, as a light tan amorphous solid, as thehydrochloride salt.

[0630]¹H-NMR (δ, CDCl₃): 0.90 (d, J=6, 6H), 1.19 (m, 1H), 1.6-2.0 (m,10H), 2.15 (m, 3H), 2.68 (m, 4H), 2.83 (m, 1H), 2.98 (m, 1H), 3.83 (m,2H), 4.54 (bs, 2H), 6.41 (d, J=8, 1H), 6.65 (m, 2H), 7.08 (d, J=8, 1H),7.435 (t, J=8, 1H).

[0631]¹³C-NMR (δ, CDCl₃): 20.99, 21.06, 22.42, 22.87, 23.61, 24.44,25.36, 27.34, 28.22, 35.98, 54.48, 57.44, 67.05, 70.71, 106.19, 107.36,114.54, 126.33, 126.86, 133.14, 136.24, 137.86, 156.58, 157.59, 158.82.

[0632] MS (%): 394 (parent+1, 100).

[0633] HRMS Calc'd. for C₂₅H₃₆N₃O: C 394.2858. Found: 394.2893.

EXAMPLE 51

[0634]6-{4-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5g]isoquinolin-6-yl)-ethoxy]-naphthalen-1-yl}-pyridin-2-ylamine

[0635] Prepared as in Example 12, in 65% yield, as an amorphous solid.

[0636]¹H-NMR (d, CDCl₃): 2.85 (m, 2H), 2.93 (m, 2H), 3.15 (t, J=6, 2H),3.77 (s, 2H), 4.415 (t, J=6, 2H), 4.56 (bs, 2H), 5.87 (s, 2H), 6.48 (s,1H), 6.51 (d, J=8, 1H), 6.56 (s, 1H), 6.88 (m, 2H), 7.4-7.6 (m, 4H),8.10 (m, 1H), 8.31 (m, 1H).

[0637]¹³C-NMR (d, CDCl₃): 28.9, 51.4, 566.4, 56.6, 66.8, 100.5, 104.3,106.4, 106.5, 108.3, 115.3, 122.1, 125.1, 125.6, 125.8, 126.6, 126.8,127.2, 131.3, 132.1, 138.0, 145.7, 146.0, 154.6, 157.6, 157.8.

[0638] MS (%): 440 (parent+1, 100).

[0639] HRMS Calc'd. for C₂₇H₂₆N₃O₃: 440.1974. Found: 440.1971.

EXAMPLE 52

[0640] 6-[7-(2-Dimethylamino-ethoxy)-indan-4-yl]-pyridin-2-ylamine

[0641] Prepared as in Example 37, starting with 1-indanol, in 57% yield,mp 215°-21 8° C., as the hydrochloride salt.

[0642]¹H-NMR (d, CDCl₃): 2.00 (quin, J=6, 2H), 2.32 (s, 6H), 2.72 (t,J=6, 2H), 2.86 (t, J=7, 2H), 3.06 (t, J=7, 2H), 4.10 (t, J=6, 2H), 4.63(bs, 2H), 6.32 (d, J=8, 1H), 6.71 (d, J=8, 1H), 6.76 (d, J=8, 1H), 7.39(m, 2H).

[0643]¹³C-NMR (d, CDCl₃): 25.31, 29.56, 33.78, 46.07, 58.24, 66.46,106.02, 109.34, 112.88, 127.97, 129.99, 132.66, 137.80, 144.30, 155.24,157.34, 158.08.

[0644] MS (%): 298 (parent+1, 100).

[0645] Anal. Calc'd. for C₁₈H₂₃N₃O.2HCl.1/2H₂O: C 56.99, H 6.91, N11.08. Found: C 56.59, H 6.93, N 11.01.

EXAMPLE 53

[0646] 6-[7-(2-Diisopropylamino-ethoxy)-indan-4-yl]-pyridin-2-ylamine

[0647] Prepared as in Example 37, in 63% yield, as a tan amorphoussolid, as the hydrochloride salt.

[0648]¹H-NMR (d, CDCl₃): 1.06 (d, J=6, 12H), 2.02 (quin, J=7, 2H), 2.875(m, 4H), 3.10 (m, 4H), 3.98 (m, 2H), 4.52 (bs, 2H), 6.35 (d, J=8, 1H),6.74 (d, J=8, 1H), 6.80 (d, J=8, 1H), 7.41 (m, 2H).

[0649]¹³C-NMR (d, CDCl₃): 20.71, 25.33, 29.56, 33.81, 44.65, 49.86,68.95, 105.94, 109.31, 112.99, 127.99, 129.76, 132.48, 137.83, 144.27,155.39, 157.45, 157.94.

[0650] MS (%): 354 (parent+1, 100).

[0651] Anal. Calc'd. for C₂₂H₃₁N₃O.2HCl.H₂O.1/2(C₄H₁₀O): C 59.87, H8.37, N 8.73. Found: C 59.69, H 8.19, N 8.75.

EXAMPLE 54

[0652] 6-[7-(2-Morpholin4-yl-ethoxy)-indan-4-yl]-pyridin-2-ylamine

[0653] Prepared as in Example 37, in 93% yield, as a tan amorphoussolid.

[0654]¹H-NMR (d, CDCl₃): 2.01 (quin, J=7, 2H), 2.58 (m, 4H), 2.79 (t,J=6, 2H), 2.86 (t, J=7, 2H), 3.09 (t, J=7, 2H), 3.71 (m, 4H), 4.14 (t,J=6, 2H), 4.57 (bs, 2H), 6.33 (d, J=8, 1H), 6.72 (d, J=8, 1H), 6.79 (d,J=8, 1H), 7.40 (m, 2H).

[0655]¹³C-NMR (d, CDCl₃): 25.20, 29.50, 33.73, 54.10, 57.56, 66.18,66.92, 105.89, 109.33, 112.81, 127.91, 130.07, 132.59, 137.71, 144.29,155.04, 157.26, 157.95.

[0656] MS (%): 340 (parent+1, 100).

[0657] Anal. Calc'd. for C₂₀H₂₅N₃O₂: C 70.77, H 7.42, N 12.38. Found: C70.49, H 7.58, N 12.02.

EXAMPLE 55

[0658]6-{7-[2-(7,8-Dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl)-ethoxy]-indan-4-yl}-pyridin-2-ylamine

[0659] Prepared as in Example 37, in 81% yield, as a foam.

[0660]¹H-NMR (d, CDCl₃): 2.04 (quin, J=7, 2H), 2.8-3.0 (m, 8H), 3.11 (t,J=7, 2H), 3.70 (s, 2H), 4.24 (t, J=6, 2H), 4.63 (bs, 2H), 5.86 (s, 2H),6.35 (d, J=8, 1H), 6.48 (s, 1H), 6.55 (s, 1H), 6.76 (d, J=8, 1H), 6.81(d, J=8, 1H), 7.4-7.5 (m, 2H).

[0661]¹³C-NMR (d, CDCl₃): 25.25, 28.83, 29.56, 33.75, 51.24, 56.29,56.46, 66.49, 100.52, 105.99, 106.39, 108.34, 109.30, 112.86, 126.89,127.28, 127.98, 129.88, 132.59, 137.82, 144.32, 145.63, 145.99, 155.12,157.13, 157.87.

[0662] MS (%): 430 (parent+1, 100).

[0663] HRMS Calc'd. for C₂₆H₂₈N₃O₃: 430.2160. Found: 430.2131.

EXAMPLE 56

[0664]6-{7-[2-(4-Methyl-piperazin-1-yl)ethoxy]-indan-4-yl}-pyridin-2-ylamine

[0665] Prepared as in Example 37, in 81% yield, as a tan solid, mp >205°C., as the hydrochloride salt.

[0666]¹H-NMR (d, CDCl₃): 2.00 (quin, J=7, 2H), 2.26 (s, 3H), 2.4-2.7 (m,8H), 2.8-2.9 (m, 4H), 3.08 (t, J=7, 2H), 4.13 (t, J=6, 2H), 4.49 (bs,2H), 6.34 (d, J=8, 1H), 6.71 (d, J=8, 1H), 6.79 (d, J=8, 1H), 7.40 (t,J=8, 1H).

[0667]¹³C-NMR (d, CDCl₃): 25.20, 29.46, 33.72, 45.96, 53.55, 55.04,57.08, 66.24, 105.85, 109.32, 112.86, 127.86, 129.97, 132.61, 137.69,144.23, 155.08, 157.31, 157.87.

[0668] MS (%): 353 (parent+1, 100).

[0669] HRMS Calc'd. for C₂₁H₂₉N₄O: 353.2345. Found: 353.2341.

EXAMPLE 57

[0670]6-{7-[2-(tert-Butyl-methyl-amino)-ethoxy]-indan-4-yl}-pyridin-2-ylamine

[0671] Prepared as in Example 37, in 96% yield, mp foams at 110° C., asthe hydrochloride salt.

[0672]¹H-NMR (d, CDCl₃): 1.10 (s, 9H), 2.005 (quin, J=7, 2H), 2.34 (s,3H), 2.81 (t, J=7, 2H), 2.87 (t, J=7, 2H), 3.07 (t, J=7, 2H), 4.09 (t,J=7, 2H), 4.79 (bs, 2H), 6.34 (d, J=8, 1H), 6.75 (m, 2H), 7.40 (m, 2H).

[0673]¹³C-NMR (d, CDCl₃): 14.11, 25.26, 25.89, 29.47, 32.51, 33.65,36.50, 50.31, 67.47, 106.04, 109.13, 112.84, 128.01, 129.50, 132.33,137.81, 144.07, 155.34, 156.10, 157.24, 158.05.

[0674] MS (%): 340 (parent+1, 100).

[0675] HRMS Calc'd. for C₂₁H₃N₃O: 340.2381. Found: 340.2389.

EXAMPLE 58

[0676]6-{7-[2-(4-Dimethylamino-piperidin-1-yl)-ethoxy]-indan-4-yl}-pyridin-2-ylamine

[0677] Prepared as in Example 37, in 100% yield, as an amorphous solid,as the hydrochloride salt.

[0678]¹H-NMR (d, CDCl₃): 1.60 (m, 2H), 1.82 (m, 3H), 2.00 (quin, J=7,2H), 2.13 (m, 2H), 2.27 (s, 6H), 2.80 (t, J=6, 2H), 2.85 (t, J=7, 2H),3.06 (t, J=7, 2H), 4.15 (t, J=6, 2H), 4.75 (bs, 2H), 6.35 (d, J=8, 1H),6.72 (d, J=8, 1H), 6.76 (d, J=8, 1H), 7.405 (m, 2H).

[0679]¹³C-NMR (d, CDCl₃): 25.22, 27.83, 29.47, 32.47, 33.63, 41.37,53.51, 56.96, 61.98, 66.14, 106.04, 109.30, 112.86, 127.99, 129.77,132.49, 137.81, 144.16, 155.09, 155.91, 157.20, 158.00.

[0680] MS (%): 381 (parent+1, 100).

[0681] HRMS Calc'd. for C₂₃H₃₃N₄O: 381.2669. Found: 381.2654.

EXAMPLE 59

[0682] 6-[7-(2-Pyrrolidin-1-yl-ethoxy)-indan-4-yl]-pyridin-2-ylamine

[0683] Prepared as in Example 37, in 72% yield, mp 113°-117° C., as thehydrochloride salt.

[0684]¹H-NMR (d, CDCl₃): 1.77 (m, 4H), 2.01 (uqin, J=7, 2H), 2.62 (m,4H), 2.89 (m, 4H), 3.08 (t, J=7, 2H), 4.15 (t, J=6, 2H), 4.52 (bs, 2H),6.34 (d, J=8, 1H), 6.73 (d, J=8, 1H), 6.79 (d, J=8, 1H), 7.40 (m, 4H).

[0685]¹³C-NMR (d, CDCl₃): 23.53, 25.30, 29.57, 33.78, 54.88, 54.98,67.37, 105.94, 109.36, 112.99, 127.97, 129.94, 132.65, 137.80, 144.28,155.27, 157.45, 157.95.

[0686] MS (%): 324 (parent+1, 100).

[0687] Anal. Calc'd. for C₂₀H₂₅N₃O.2HCl.3/2H₂O: C 56.74, H 7.14, N 9.92.Found: C 56.40, H 7.07, N 9.84.

EXAMPLE 60

[0688] 6-[7-[2-(N-Benzyl,N-methyl-amino)ethoxy)]-indan4-yl]-pyridin-2-ylamine

[0689] Prepared as in Example 37, in 48% yield, mp 110°-130° C., as thehydrochloride salt.

[0690]¹H-NMR (d, CDCl₃): 2.045 (quin; J=7, 2H), 2.37 (s, 3H), 2.87 (t,J=6, 2H), 2.92 (t, J=7, 2H), 3.13 (t, J=7, 2H), 3.65 (s, 2H), 4.16 (t,J=6, 2H), 4.65 (bs, 2H), 6.34 (d, J=8, 1H), 6.74 (d, J=8, 1H), 6.82 (d,J=8, 1H), 7.2-7.6 (m, 7H).

[0691]¹³C-NMR (d, CDCl₃): 25.37, 29.67, 33.86, 43.04, 55.84, 62.74,66.54, 106.04, 109.25, 112.94, 127.07, 128.04, 128.32, 129.06, 129.98,132.62, 137.84, 139.06, 144.34, 155.34, 157.42, 158.13.

[0692] MS (%): 374 (parent+1, 100).

[0693] Anal. Calc'd. for C₂₄H₂₇N₃O.2HCl: C 64.57, H 6.55, N 9.41. Found:C 64.52, H 6.88, N 9.38.

EXAMPLE 61

[0694]6-[7-[(4-Phenethylpiperazin-1-yl)-ethoxy]-indan-4-yl]-pyridin-2-ylamine

[0695] Prepared as in Example 37, in 41% yield, mp 105°-130° C., as thehydrochloride salt.

[0696]¹H-NMR (d, CDCl₃): 1.995 (quin, J=7, 2H), 2.5-2.9 (m, 16H), 3.08(t, J=7, 2H), 4.13 (t, J=6, 2H), 4.61 (bs, 2H), 6.30 (d, J=8, 1H), 6.70(d, J=8, 1H), 6.76 (d, J=8, 1H), 7.2-7.5 (m, 7H).

[0697]¹³C-NMR (d, CDCl₃): 25.31, 29.57, 33.60, 33.82, 53.20, 53.69,57.22, 60.55, 66.27,7 105.95, 109.35, 112.82, 126.02, 128.00, 128.37,128.66, 128.69, 130.07, 132.62, 137.76, 140.29, 144.30, 155.17, 157.34,158.10.

[0698] MS (%): 443 (parent+1, 100).

[0699] Anal. Calc'd. for C₂₈H₃₄N₄O.2HCl: C 65.24, H 7.04, N 10.87.Found: C 65.03, H 7.23, N 10.81.

EXAMPLE 62

[0700]6-[7-[(4-Isobutylpiperazin-1-yl)-ethoxy]-indan-4-yl]-pyridin-2-ylamine

[0701] Prepared as in Example 37, in 92% yield, mp 170°-190° C., as thehydrochloride salt.

[0702]¹H-NMR (d, CDCl₃): 0.85 (d, J=6, 6H), 1.73 (m, 1H), 2.0 (m, 2H),2.04 (d, J=7, 2H), 2.40 (m, 4H), 2.60 (m, 4H), 2.79 (t, J=7, 2H), 2.84(t, J=7, 2H), 3.07 (t, J=7, 2H), 4.13 (t, J=6, 2H), 4.57 (bs, 2H), 6.32(d, J=8, 1H), 6.70 (d, J=8, 1H), 6.76 (d, J=8, 1H), 7.38 (m, 2H).

[0703]¹³C-NMR (d, CDCl₃): 25.16, 25.28, 29.45, 33.69, 53.47, 53.70,57.16, 66.22, 66.84, 105.82, 109.32, 112.79, 127.88, 129.96, 132.56,137.65, 144.20, 155.12, 157.33, 157.92.

[0704] MS (%): 395 (parent+1, 100).

[0705] Anal. Calc'd. for C₂₄H₃₄N₄O.3HCl.H₂O: C 55.23, H 7.53, N 10.73.Found: C 55.51, H 7.72, N 10.46.

EXAMPLE 63

[0706] 6-[4-(2-Amino-cyclohexyloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0707] Prepared as in Example 24, in 96% yield, mp 218°-230° C., as thehydrochloride salt.

[0708]¹H-NMR (d, CDCl₃): 1.36 (m, 4H), 1.76 (m, 2H), 2.0-2.4 (m, 2H),3.05 (m, 1H), 4.10 (m, 1H), 4.62 (bs, 2H), 6.45 (d, J=8, 1H), 6.84 (d,J=8, 1H), 6.93 (d, J=8, 1H), 7.4-7.6 (m, 4H), 8.08 (m, 1H), 8.32 (m,1H).

[0709]¹³C-NMR (d, CDCl₃): 24.30, 24.49, 29.60, 33.36, 54.87, 83.58,106.14, 106.51, 115.12, 122.07, 125.00, 125.71, 126.50, 126.57, 127.12,131.32, 132.28, 137.94, 153.86, 157.64, 158.05.

[0710] MS (%): 334 (parent+1, 100).

[0711] Anal. Calc'd. for C₂₁H₂₃N₃O.2HCl.1/4H₂O.1/2(C₄H₈O): C 60.73, H6.54, N 9.24. Found: C 60.63, H 6.58, N 9.10.

EXAMPLE 64

[0712] 6-[4-(Piperidin-3-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0713] Prepared as in Example 24, in 38% yield, mp 164°-185° C., as thehydrochloride salt.

[0714]¹H-NMR (d, CDCl₃): 1.2-1.4 (m, 1H), 1.54 (m, 1H), 1.69 (m, 1H),1.91 (m, 1H), 2.07 (m, 1H), 2.45 (m, 1H), 2.55 (m, 1H), 2.8-3.0 (m, 1H),3.04 (m, 1H), 3.25 (m, 1H), 3.92 (m, 2H), 4.71 (bs, 2H), 6.43 (d, J=8,1H), 6.78 (d, J=8, 1H), 6.82 (d, J=8, 1H), 7.4-7.6 (m, 4H), 8.08 (m,1H), 8.29 (m, 1H).

[0715]¹³C-NMR (d, CDCl₃): 25.72, 27.81, 36.93, 46.67, 49.84, 71.04,103.97, 106.55, 115.05, 122.04, 125.02, 125.60, 125.73, 126.60, 127.17,131.17, 132.05, 137.95, 154.79, 157.60, 158.13.

[0716] MS (%): 334 (parent+1, 100).

[0717] Anal. Calc'd. for C₂₁H₂₃N₃O.2HCl1/2H₂O.1/4(C₄H₈O): C 60.41, H6.45, N 9.61. Found: C 60.33, H 6.50, N 9.28.

EXAMPLE 65

[0718]6-[4-(1-Isobutyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0719] Prepared as in Example 24, in 57% yield, mp 133°-148° C., as thehydrochloride salt.

[0720]¹H-NMR (d, CDCl₃): 0.91 (d, J=6, 6H), 1.65 (septet, J=6, 1H), 2.37(d, J=7, 2H), 3.18 (m, 2H), 3.98 (m, 2H), 4.56 (bs, 2H), 5.01 (m, 1H),6.47 (d, J=8, 1H), 6.59 (d, J=8, 1H), 6.84 (d, J=8, 1H), 7.3-7.5 (m,4H), 8.09 (m, 1H), 8.30 (m, 1H).

[0721]¹³C-NMR (d, CDCl₃): 20.89, 27.19, 62.17, 67.03, 68.54, 104.60,106.61, 115.26, 122.16, 125.20, 125.66, 125.73, 126.78, 127.05, 131.87,132.25, 138.04, 152.89, 157.70, 158.04.

[0722] MS (%): 348 (parent+1, 100).

[0723] Anal. Calc'd. for C₂₂H₂₅N₃O.2HCl.1/2H₂O. (C₄H₈O): C 60.35, H7.01, N 8.12. Found: C 60.50, H 7.05, N 8.00.

EXAMPLE 66

[0724]6-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0725] Prepared as in Example 24, in 93% yield, mp 260°-275° C., as thehydrochloride salt.

[0726]¹H-NMR (d, CDCl₃): 2.0-2.3 (m, 8H), 2.305 (s, 3H), 3.15 (m, 2H),4.59 (bs, 2H), 4.75 (m, 1H), 6.43 (d, J=8, 1H), 6.79 (d, J=8, 1H), 6.84(d, J=7, 1H), 7.4-7.6 (m, 4H), 8.09 (m, 1H), 8.29 (m, 1H).

[0727]¹³C-NMR (d, CDCl₃): 25.81, 35.97, 40.52, 59.84, 69.09, 104.46,106.38, 115.09, 122.16, 125.00, 125.70, 126.31, 126.47, 127.12, 130.74,132.39, 137.89, 153.06, 157.79, 158.00.

[0728] MS (%): 360 (parent+1, 100).

[0729] Anal. Calc'd. for C₂₃H₂₅N₃O.1/2(CO₂) (i.e., ½ carboxylate): C73.99, H 6.61, N 11.02. Found: C 74.00, H 6.65, N 10.85.

EXAMPLE 67

[0730]6-[4-(1-Furan-2-ylmethyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0731] Prepared as in Example 24, in 50% yield, mp 75°-90° C., as thehydrochloride salt.

[0732]¹H-NMR (δ, CDCl₃): 3.34 (m, 2H), 3.71 (s, 2H), 3.97 (m, 2H), 4.58(bs, 2H), 5.01 (m, 1H), 6.20 (m, 1H), 6.30 (m, 1H), 6.48 (d, J=8, 1H),6.57 (d, J=8, 1H), 6.84 (d, J=7, 1H), 7.3-7.5 (m, 5H), 8.09 (m, 1H),8.30 (m, 1H).

[0733]¹³C-NMR (δ, CDCl₃): 54.99, 61.12, 66.84, 104.54, 106.57, 107.86,110.06, 115.18, 122.07, 125.15, 125.63, 126.72, 126.95, 131.79, 132.16,138.01, 142.28, 151.47, 152.74, 157.49, 157.90.

[0734] MS (%): 372 (parent+1, 100).

[0735] HRMS Calc'd. for C₂₃H₂₂N₄O₂: 372.1712. Found: 372.1690.

EXAMPLE 68

[0736]6-[4-(Pyrrolidin-2-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0737] Prepared as in Example 48, usingR-N-t-BOC-pyrrolidine-2-methanol, followed by conversion to the tosylateand alkylaton with 2-(2,5-dimethylpyrrolyl)-6-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-pyridine, then deblocking to afford a tan,amorphous solid, in 95% yield, as the hydrochloride salt.

[0738]¹H-NMR (δ, CDCl₃): 1.63 (m, 3H), 1.74 (m, 4H), 1.90 (m, 1H), 2.68(m, 4H), 2.96 (AB, 2H), 3.50 (m, 1H), 3.90 (m, 2H), 4.56 (bs, 2H), 6.37(d, J=8, 1H), 6.63 (d, J=7, 1H), 6.67 (d, J=8, 1H), 7.07 (d, J=8, 1H),7.40 (t, J=8, 1H).

[0739]¹³C-NMR (δ, CDCl₃): 22.31, 22.77, 23.57, 25.28, 27.91, 28.13,46.50, 57.42, 70.65, 106.06, 107.50, 114.32, 126.16, 126.80, 133.51,136.22, 137.67, 156.28, 157.63, 158.72.

[0740] MS (%): 324 (parent+1, 100).

[0741] HRMS Calc'd. for C₂₀H₂₆N₃O: 324.2076. Found: 324.2055.

EXAMPLE 69

[0742]6-[4-(1-Methyl-pyrrolidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0743] Prepared as in Example 24, using S-(−)-1-methyl-2-pyrrolidinemethanol to afford, after deblocking in 88% yield, a tan solid, mp80°-95° C., α_(D)=−36.47° (c=1, CH₂Cl₂).

[0744]¹H-NMR (δ, CDCl₃): 1.8 (m, 2H), 1.9 (m, 1H), 2.12 (m, 1H), 2.34(m, 1H), 2.56 (s, 3H), 2.83 (m, 1H), 3.13 (m, 1H), 4.13 (AB, 2H), 4.63(bs, 2H), 6.41 (d, J=8, 1H), 6.83 (m, 2H), 7.46 (m, 4H), 8.10 (m, 1H),8.31 (m, 1H).

[0745]¹³C-NMR (δ, CDCl₃): 23.00, 28.92, 41.87, 57.79, 64.27, 71.57,104.06, 106.45, 115.09, 122.07, 124.97, 125.64, 125.73, 126.01, 126.53,127.20, 131.29, 132.06, 137.89, 154.78, 157.69, 158.07.

[0746] MS (%): 334 (parent+1, 100).

[0747] Anal. Calc'd. for C₂₁H₂₃N₃O.1/3H₂O: C 74.31, H 7.03, N 12.38.Found: C 74.11, H 7.19, N 12.22.

EXAMPLE 70

[0748]6-[4-(2-Amino-cyclohexyloxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine

[0749] Prepared as in Example 48, via the following four-step sequence:2-(2,5-dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridinewas first alkylated with 2-chlorocyclohexanone, using potassiumcarbonate as the base and a catalytic amount of sodium iodide, indimethylformamide at 80° C. for 24 hours, in 92% yield. The resultingketone was converted to the oxime methyl ether usingO-methylhydroxylamine hydrochloride and triethylamine in methanol atreflux for 16 h in 81% yield. The oxime ether was then reduced to theamine using borane methyl sulfide in tetrahydrofuran at reflux for 2days, followed by refluxing in ethanol with sodium carbonate and cesiumfluoride for 16 hours, in 12% yield. The amine was then deblocked withhydroxylamine hydrochloride in refluxing aqueous ethanol to afford thedesired final product in 89% yield as a tan solid after conversion tothe hydrochloride salt.

[0750]¹H-NMR (δ, CDCl₃): 1.2-1.5 (m, 6H), 1.6-1.9 (m, 6H), 2.70 (m, 4H),2.94 (m, 1H), 4.49 (m, 1H), 4.55 (bs, 2H), 6.39 (d, J=8, 1H), 6.65 (d,J=8, 1H), 6.72 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.43 (t, J=8, 1H).

[0751]¹³C-NMR (δ, CDCl₃): 20.3, 22.4, 22.37, 23.7, 23.9, 27.4, 28.2,30.9, 52.1, 75.8, 106.1, 108.6, 114.4, 126.8, 127.0, 133.1, 136.5,137.7, 154.9, 157.6, 158.7.

[0752] MS (%): 338 (parent+1, 100).

[0753] HRMS Calc'd. for C₂₁H₂₈N₃O: 338.2232. Found: 338.2256.

EXAMPLE 71

[0754] 6-[4-(Azetidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0755] Prepared as in Example 24 using L-azetidine-2-carboxylic acid asthe precursor to N-t-BOC-azetidine-2-methanol as the reagent to add to2-(2,5-dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine, followed byremoval of blocking groups to afford 45% yield of a solid, mp 135°-150°C.

[0756]¹H-NMR (δ, CDCl₃): 2.33 (m, 1H), 2.43 (m, 1H), 3.4 (bs, 1H), 3.54(m, 1H), 3.67 (m, 1H), 4.20 (m, 2H), 4.37 (m, 1H), 4.625 (bs, 2H), 6.45(d, J=8, 1H), 6.84 (m, 2H), 7.45 (m, 4H), 8.10 (m, 1H), 8.31 (m, 1H).

[0757]¹³C-NMR (δ, CDCl₃): 23.93, 44.25, 57.45, 72.10, 104.39, 106.54,115.15, 122.00, 125.04, 125.63, 125.73, 126.63, 127.15, 131.50, 132.06,137.95, 154.59, 157.62, 158.03.

[0758] MS (%): 306 (parent+1, 100).

[0759] Anal. Calc'd. for C₁₉H₁₉N₃O.2HCl.3/2H₂O.1/2(C₄H₈O): C 56.13, H6.28, N 9.35. Found: C 56.24, H 6.52, N 9.05.

EXAMPLE 72

[0760]6-[4-(1-Pyridin-3-ylmethyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0761] Prepared as in Example 24, in 24% yield, mp 150°-180° C., as thehydrochloride salt.

[0762]¹H-NMR (δ, CDCl₃): 3.29 (m, 2H), 3.71 (s, 2H), 3.92 (m, 2H), 4.57(bs, 2H), 5.005 (m, 1H), 6.47 (d, J=8, 1H), 6.56 (d, J=8, 1H), 6.83 (d,J=7, 1H), 7.24 (m, 1H), 7.39 (d, J=8, 1H), 7.5-7.6 (m, 4H), 7.63 (m,1H), 8.09 (m, 1H), 8.29 (m, 1H), 8.50 (m, 1H), 8.54 (s, 1H).

[0763]¹³C-NMR (δ, CDCl₃): 60.9, 61.4, 66.8, 104.5, 106.6, 115.1, 122.0,123.4, 125.5, 125.7, 126.7, 126.9, 132.0, 132.2, 133.3, 136.0, 138.0,148.7, 149.8, 152.7, 157.5, 158.0.

[0764] MS (%): 383 (parent+1, 100).

[0765] Anal. Calc'd. for C₂₄H₂₂N₄O.3HCl.3H₂O.1/3(C₄H₈O): C 53.39, H5.95, N 9.83. Found: C 53.22, H 6.18, N 9.43.

EXAMPLE 73

[0766] 6-[4-(Azetidin-3-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0767] Prepared as in Example 24, in which N-BOC azetidine-3-methanolwas added to 2-(2,5-dimethylpyrrolyl)-6-(4-fluoronaphth-1-yl)pyridine asin Example 24D followed by sequential removal of the BOC and pyrrolylprotecting groups, with the final step proceeding in 75% yield, in 75%yield, mp 88°-110° C., as the hydrochloride salt.

[0768]¹H-NMR (δ, CDCl₃): 3.27 (m, 1H), 3.64 (m, 2H), 3.78 (m, 2H), 4.25(d, J=6, 2H), 4.63 (bs, 2H), 6.45 (d, J=8, 1H), 6.83 (m, 2H), 7.4-7.6(m, 4H), 8.09 (m, 1H), 8.29 (m, 1H).

[0769]¹³C-NMR (δ, CDCl₃): 34.2, 49.8, 69.8, 104.2, 106.5, 115.1, 122.0,125.0, 125.4, 125.6, 125.7, 126.6, 127.1, 131.4, 132.0, 138.0, 154.7,157.6, 158.1.

[0770] MS (%): 306 (parent+1, 100).

[0771] Anal. Calc'd. for C₁₉H₁₉N₃O.2HCl.2H₂O.3/2(C₄H₈O): C 57.25, H7.00, N 8.04. Found: C 57.47, H 7.14, N 8.21.

EXAMPLE 74

[0772]6-[4-(1-Pyridin-2-ylmethyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0773] Prepared as in Example 24, in 24% yield, mp 97°-120° C., as thehydrochloride salt from tetrahydrofuran.

[0774]¹H-NMR (δ, CDCl₃): 3.42 (m, 2H), 3.89 (s, 2H), 4.015 (m, 2H), 4.62(bs, 2H), 5.045 (m, 1H), 6.47 (d, J=8, 1H), 6.57 (d, J=8, 1H), 6.82 (d,J=7, 1H), 7.16 (m, 1H), 7.3-7.5 (m, 5H), 7.64 (t, J=8, 1H), 8.07 (m,1H), 8.30 (m, 1H), 8.55 (m, 1H). ¹³C-NMR (δ, CDCl₃): 61.62, 64.89,67.10, 104.52, 106.64, 115.14, 122.09, 122.13, 122.42, 125.18, 125.60,126.73, 126.92, 131.75, 132.16, 136.58, 138.04, 149.30, 152.77, 157.41,157.76, 157.96.

[0775] MS (%): 383 (parent+1, 100).

[0776] Anal. Calc'd. for C₂₄H₂₂N₄O.3HCl.7/4H₂O: C 55.08, H 5.49, N10.70. Found: C 55.44, H 5.61, N 10.31.

EXAMPLE 75

[0777]6-[4-(N-methyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine:Prepared as in Example 24, using formaldehyde in methanol with sodiumcyanoborohydride at room temperature, in 30% yield, mp 240°-255° C., asthe hydrochloride salt from tetrahydrofuran.

[0778]¹H-NMR (δ, CDCl₃): 2.45 (s, 3H), 2.75 (bs, 2H), 3.30 (m, 2H), 3.99(m, 2H), 4.96 (m, 1H), 6.47 (d, J=8, 1H), 6.55 (d, J=8, 1H), 6.80 (d,J=7, 1H), 7.3-7.5 (m, 4H), 8.03 (m, 1H), 8.28 (m, 1H).

[0779]¹³C-NMR (δ, CDCl₃): 45.81, 63.07, 66.19, 104.44, 106.84, 115.08,121.97, 125.23, 125.43, 125.57, 126.76, 126.87, 131.82, 132.15, 138.14,152.56, 157.13, 158.05.

[0780] MS (%): 306 (parent+1, 100).

[0781] Anal. Calc'd. for C₁₉H₁₉N₃O.2HCl.2H₂O: C 55.08, H 6.08, N 10.14.Found: C 55.34, H 6.01, N 9.82.

EXAMPLE 76

[0782]6-[4-(N-Isopropyl-azetidin-3-yloxy)-naphthalen-1-yl]-pyridin-2-ylamine

[0783] Prepared as in Example 24, as a byproduct of the reaction usedfor preparation of Example 75, from acetone in the methanol, in 19%yield, mp 120°-135° C., as the hydrochloride salt from tetrahydrofuran.

[0784]¹H-NMR (δ, CDCl₃): 0.99 (d, J=6, 6H), 2.49 (septet, J=6, 1H), 3.25(m, 2H), 3.96 (m, 2H), 4.65 (bs, 2H), 4.97 (m, 1H), 6.48 (d, J=8, 1H),6.60 (d, J=8, 1H), 6.81 (d, J=6, 1H), 7.4-7.5 (m, 4H), 8.03 (m, 1H),8.27 (m, 1H).

[0785]¹³C-NMR (δ, CDCl₃): 19.30, 50.44, 58.78, 65.40, 104.52, 106.81,115.12, 122.00, 125.20, 125.45, 125.56, 126.73, 126.89, 131.78, 132.15,138.15, 152.66, 157.21, 158.02.

[0786] MS (%): 332 (parent+1, 100).

[0787] Anal. Calc'd. for C₂₁H₂₃N₃O.2HCl.2H₂O: C 57.02, H 6.61, N 9.50.Found: C 57.04, H 6.51, N 9.29.

EXAMPLE 77

[0788]6-[4-(2-Dimethylamino-ethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-pyridin-2-ylamine

[0789] Prepared as in Example 37, using4-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene as the startingmaterial, which was prepared as follows: 8 g (71.4 mmol) 2-hydroxypyrone(Syn. Commun.,5, 461, (1975)) and 20 mL cycloheptene were reacted in asealed tube at 150° C. for 24 h to give1-oxo-3,4,6,7,8,9-hexahydro-5H-benzocycloheptene in 49.5% yield,followed by reaction with isopropenyl acetate to afford the enol acetateand treatment with 2,3-dichloro-5,6-dicyanobenzoquinone at 90° C. for1.5 h (see J. Med. Chem., 37, 3803 (1994)) to afford4-acetoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene in 69% yield as anoil. Hydrolysis with 3.7 equivalents of powdered potassium hydroxide inethanol at room temperature for 2 h gave a 44% yield of the desired4-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene after purification bycolumn chromatography as a white solid. The remaining steps in thesequence then followed Example 48. The final step proceeded in 89% yieldto give the product as an amorphous solid as the hydrochloride salt fromether.

[0790]¹H-NMR (δ, CDCl₃): 1.58 (m, 4H), 1.79 (m, 2H), 2.34 (s, 6H), 2.75(m, 4H), 2.93 (m, 2H), 4.06 (t, J=6, 2H), 4.48 (bs, 2H), 6.39 (d, J=8,1H), 6.62 (d, J=8, 1H), 6.74 (d, J=8, 1H), 7.10 (d, J=8, 1H), 7.41 (d,J=8, 1H).

[0791]¹³C-NMR (δ, CDCl₃): 25.51, 27.36, 27.75, 31.21, 32.46, 46.03,58.35, 67.43, 105.94, 109.95, 114.72, 127.58, 132.85, 133.74, 137.54,142.88, 155.43, 157.74, 159.32.

[0792] MS (%): 326 (parent+1, 100).

1. A compound of the formula

wherein ring A is a fused 5-7 membered saturated or unsaturated ringwherein from zero to two of the ring members are heteroatoms selected,independently, from nitrogen, oxygen and sulfur, with the proviso thatno two adjecent ring members can both be heteroatoms; X is oxygen or abond; n is an interger from two to six; and R¹ and R² are selected,independently, from (C₁-C₆) alkyl, aryl, tetrahydronaphthalene andaralkyl, wherein said aryl and the aryl moiety of said aralkyl is phenylor naphthyl and the alkyl moiety is straight or branched and containsfrom 1 to 6 carbon atoms, and wherein said (C₁-C₆) alkyl, said aryl,said tetrahydronaphthalene and the aryl moiety of said aralkyl mayoptionally be substituted with from one to three substituents,preferably from zero to two substituents, that are selected,independently, from halo (e.g., chloro, fluoro, bromo, iodo), nitro,hydroxy, cyano, amino, (C₁-C₄) alkoxy, and (C₁-C₄) alkylamino; or R¹ andR² form, together with the nitrogen to which they are attached, apiperazine, piperidine or pyrrolidine ring or an azabicyclic ringcontaining from 6 to 14 ring members, from 1 to 3 of which are nitrogenand the rest of which are carbon; and wherein said piperazine,azetidine, piperidine and pyrrolidine rings may optionally besubstituted with one or more substituents, preferably with from zero totwo substituents that are selected, independently, from (C₁-C₆)alkyl,amino, (C₁-C₆) alkylamino, [di-(C₁-C₆)alkyl]amino, phenyl substituted 5to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogenatoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl,phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of anyof the foregoing substituents may optionally be substituted with one ormore substituents, preferably with from zero to two substituents, thatare selected, independently, from halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,nitro, amino, cyano, CF₃ and OCF₃; also R¹ or R² may be connected ontothe (CH2)_(n) group to form a ring of from 4 to 7 members; and thepharmaceutically acceptable salt of such compounds.
 2. A compoundaccording to claim 1 , wherein NR¹R² is an optionally substitutedpiperidine, azetidine, piperazine or pyrrolidine ring or a3-aza-bicyclo[3.1.0]hex-6-ylamine ring; and wherein said piperazine,azetidine, piperidine and pyrrolidine rings may optionally besubstituted with one or more substituents, preferably with from zero totwo substituents that are selected, independently, from (C₁-C₆)alkyl,amino, (C₁-C₆) alkylamino, [di-(C₁-C₆)alkyl]amino, phenyl substituted 5to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogenatoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl,phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of anyof the foregoing substituents may optionally be substituted with one ormore substituents, preferably with from zero to two substituents, thatare selected, independently, from halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,nitro, amino, cyano, CF₃ and OCF₃.
 3. A compound according to claim 1wherein NR¹R² forms an azabicyclic ring having the formula

wherein R³ and R⁴ are selected from hydrogen, (C₁-C₆)alkyl, phenyl,naphthyl, (C₁-C₆)alkyl-C(═O), HC(═O)—, (C₁-C₆)alkoxy-(C═O)—,phenyl-C(═O)—, naphthyl-C(═O)—, and R⁶R⁷NC(═O)— wherein R⁶ and R⁷ areselected, independently, from hydrogen and (C₁-C₆)alkyl; and R⁵ isselected from hydrogen, (C₁-C₆)alkyl, phenyl, naphthyl,phenyl-(C₁-C₆)alkyl— and naphthyl(C₁-C₆)alkyl—.
 4. A pharmaceuticalcomposition for treating or preventing a condition selected from thegroup consisting of migraine inflammatory diseases, stroke, acute andchronic pain, hypovolemic shock, traumatic shock, reperfusion injury,Crohn's disease, ulcerative colitis, septic shock, depression,Parkinson's disease,, multiple sclerosis, AIDS associated dementia,neurodegenerative diseases, neuron toxicity, Alzheimer's disease,chemical dependencies and addictions, emesis, epilepsy, anxiety,psychosis, head trauma, adult respiratory distress syndrome (ARDS),morphine induced tolerance and withdrawal symptoms, inflammatory boweldisease, osteoarthritis, rheumatoid arthritis, ovulation, dilatedcardiomyopathy, acute spinal cord injury, Huntington's disease,glaucoma, macular degeneration, diabetic neuropathy, diabeticnephropathy and cancer in a mammal, comprising an amount of a compoundaccording to claim 1 that is effective in treating or preventing suchcondition and a pharmaceutically acceptable carrier.
 5. A method oftreating or preventing a condition selected from the group consisting ofmigraine inflammatory diseases, stroke, acute and chronic pain,hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease,ulcerative colitis, septic shock, multiple sclerosis, AIDS associateddementia, neurodegenerative diseases, neuron toxicity, depression,Parkinson's disease, Alzheimer's disease, chemical dependencies andaddictions, emesis, epilepsy, anxiety, psychosis, head trauma, adultrespiratory distress syndrome (ARDS), morphine induced tolerance andwithdrawal symptoms, inflammatory bowel disease, osteoarthritis,rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinalcord injury, Huntington's disease, glaucoma, macular degeneration,diabetic neuropathy, diabetic nephropathy and cancer in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 1 , that is effective in treating or preventing suchcondition.
 6. A pharmaceutical composition for inhibiting nitric oxidesynthase (NOS) in a mammal, according to claim 1 , comprising a NOSinhibiting effective amount of a compound according to claim 1 , and apharmaceutically acceptable carrier.
 7. A method of inhibiting NOS in amammal, comprising administering to said mammal a NOS inhibitingeffective amount of a compound according to claim 1 .
 8. Apharmaceutical composition for treating or preventing a conditionselected from the group consisting of migraine, inflammatory diseases,stroke, acute and chronic pain, hypovolemic shock, traumatic shock,reperfusion injury, Crohn's disease, ulcerative colitis, septic shock,multiple sclerosis, AIDS associated dementia, neurodegenerativediseases, neuron toxicity, depression, Parkinson's disease, Alzheimer'sdisease, chemical dependencies and addictions, emesis, epilepsy,anxiety, psychosis, head trauma, adult respiratory distress syndrome(ARDS), morphine induced tolerance and withdrawal symptoms, inflammatorybowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilatedcardiomyopathy, acute spinal cord injury, Huntington's disease,glaucoma, macular degeneration, diabetic neuropathy, diabeticnephropathy and cancer in a mammal, comprising a NOS inhibitingeffective amount of a compound according to claim 1 and apharmaceutically acceptable carrier.
 9. A method of treating orpreventing a condition selected from the group consisting of migraine,inflammatory diseases, stroke, acute and chronic pain, hypovolemicshock, traumatic shock, reperfusion injury, Crohn's disease, ulcerativecolitis, septic shock, multiple sclerosis, AIDS associated dementia,neurodegenerative diseases, neuron toxicity, depression, Parkinson'sdisease, Alzheimer's disease, chemical dependencies and addictions,emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratorydistress syndrome (ARDS), morphine induced tolerance and withdrawalsymptoms, inflammatory bowel disease, osteoarthritis, rheumatoidarthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury,Huntington's disease, glaucoma, macular degeneration, diabeticneuropathy, diabetic nephropathy and cancer in a mammal, comprisingadministering to said mammal a NOS inhibiting effective amount of acompound according to claim 1 .